10alpha-methyl, 9beta-steroids of the androstane series



United States Patent 17 Claims. (Cl. 260397.4)

This application is a continuation of application Ser. No. 343,197, filed Feb. 7, 1964, now abandoned, which is a continuation-in-part of application Ser. No. 805,020, filed Apr. 8, 1959, now abandoned.

This invention relates to a novel class of steroids which exhibit important pharmacological properties and/ or are useful as intermediates in the preparation of pharmacological active compounds.

All the known pharmacologically active steroids of the normal series which have a methyl substituent at the carbon atom of the nucleus have this substituent in the B position. In general these compounds are characterized in having a substantially flat or planar molecular configuration of the nucleus, with the 10fi-methyl group projecting from the plane of the nucleus.

It is now well accepted that the pharmacological activity of the compounds of the normal series is attributable to the fact that the steroid molecule is capable of conforming to the configuration of the receptor. As a result, those skilled in the art believed heretofore that steroids of the normal series are highly stereo-specific in their interaction with the receptors. Since, in general, the nuclei of the pharmacologically active compounds of the normal series are substantially fiat, it would be expected that the pharmacological activity is connected with a substantially flat structure of the nucleus and therefore it would not be expected that steroids having a substantially non-planar configuration of the nucleus would possess useful pharmacological properties.

A principal object of our invention is to prepare a new and novel class of steroids. This and other objects of our invention will be apparent from the description that follows.

Quite unexpectedly, we have discovered a novel class of steroids which behaves contrary to the aforesaid expectations in the steroid art. In contrast to the normal steroids wherein the methyl at the carbon atom 10 is in the ,8 position and the substituent at the carbon atom 9 is in the a position, in our novel class of steroids, the 10 methyl substituent is in the a position while the substituent at the carbon atom 9 is in the ,8 position.

In addition to What has been mentioned above, with respect to the configuration of the 10 methyl group, and the substituent at the carbon atom 9, there is evidence to indicate that the structure of the nucleus of our novel compounds is non-planar. It is suggested that the nucleus of our novel steroids lies in two planes which intersect at a line drawn through the 8th and 9th carbon atoms of the nucleus. While this is a theory and we do not intend to be bound thereby, nevertheless, the indications are strong that the structure of the nucleus is non-planar. In view of the stereo-specificity of the receptors, one would expect that such a deviation in the stereochernical structure of the steroid nucleus would render such steroids incapable of associating with the receptors. Consequently, it is surprising that our novel steroids possess any of the pharmacological properties of the steroids of the normal senes.

ice

The steroids of our invention even possess a specificity which manifests itself in a fewer number of pharmacological activities than those possessed by the known corresponding compounds of the normal series, and/ or exhibit new properties which are not possessed by the corresponding steroid of the normal series. In some cases, our novel steroids are unexpectedly superior in activities which are possessed in common with the corresponding compound of the normal series. Coupling the novel stereo-chemical configuration of the steroid nucleus with unexpected properties of our novel steroids, it is clear that an entirely new class of steroids has been discovered.

It is believed from all the experimental work accomplished to date that the specific IOa-methyl, 9fi-configuration of our novel steroids is the common dominant characteristic which produces the tendency for the highly specific actions thereof. Further, in this respect, the methyl, 9(3-configuration of the nucleus in cooperation with the other substituents creates the particular properties possessed by our novel steroids. Hence, the configuration of the nucleus in our novel steroids is dominant with respect to the manner in which they differentiate from the steroids of the normal series.

Those novel steroids of the present invention in which the substituents at the carbon atoms 8, 9, 10, 13 and 14 have the same stereo-configuration as those in dihydroisolumisterone (lumista 4,22 dien-3-one) are designated hereinafter as retrosteroids. Castells et al., Proc. of the Chemical Society, January 1958, page 7, has shown that dihydroisolurnisterone has the configuration 85,95,100:- methyl, 13,6, 14a.

All the novel retrosteroids of the present invention exhibit highly specific pharmacological properties with respect to the following activities: parenteral progestational, oral progestational, pregnancy maintaining, deciduomainducing, fertility stimulating, anti-arteriosclerosis, fertility inhibiting, ovulation stimulating, ovulation inhibiting, anti-estrogenic, uterotrophic, anti-uterotrophic, anabolic, renotrophic, anti-androgenic, pituitary stimulating, pituitary inhibiting, glucocorticoidal, anti-inflammatory, diuretic, etc.

With respect to the highly specific pharmacological properties exhibited by the retrosteroids in comparison with the corresponding compounds of the normal series, it will be found that the retrosteroids have fewer or none of the properties in common with the corresponding compounds of the normal series and/ or the retrosteroids may have one or more pharmacological properties which are not possessed by the corresponding compounds of the normal series. In addition the retrosteroids can be unexpectedly superior in one or more of the pharmacological properties which are common to the corresponding compounds of the normal series. One of the outstanding advantages of our novel retrosteroids is that they can be used to produce a desired pharmacological activity with a substantially reduced number of side effects in comparison with the steroids of the normal series.

To illustrate the differences between our novel retrosteroids and those of the normal series, reference will now be had to comparisons for that purpose.

As previously stated, the retrosteroids of our invention are so different in the scope and specificity of their pharmacological properties that they are not comparable with their corresponding steroids of the normal series. The following examples will make these differences readily apparent.

The compound Epi F of French Patent 1,091,734 has no glycogen storage activity and no anti-inflammatory activity while the corresponding retrosteroid of the invention has glycogen storage activity and is not anti-inflammatory.

The 17a-methylandrosta-1,4-diene-17-ol-3-one of British Patent 750,834 is anabolic, non-parenteral progestational, and not pituitary inhibiting. The corresponding ret rosteroid is anabolic, parenterally progestationally active and pituitary inhibiting.

Androst -4- ene 3,17,8-diol of United States Patent 2,911,403 is androgenic, anabolic, not pituitary inhibit ing, non-thymolytic, non-glucocorticoidal and is not antiinflammatory, whereas the corresponding retrosteroid is non-androgenic, non-anabolic, renotrophic, pituitary inhibiting, thymolytic, non-glucocorticoidal and is not antiinflammatory.

The 7-dehydroprogesterone of United States Patent 2,876,237 is progestationally active and metabolizes androgenic, while the Corresponding retrosteroid is antiestrogenic, non-progestationally active, renotrophic and non-androgenic.

17a ethynylandrosta 4,6-dien-17-o1-3-one of United States Patent 2,882,282 is parenterally progestationally active, not orally progestationally active, anabolic, androgenic and renotrophic, whereas the corresponding retrosteroid is not parenterally progestationally active, orally progestationally active, non-anabolic, nonrenotrophic, non-androgenic and anti-estrogenic. 6-dehydroprogesterone of United States Patent 2,882,282 has a decreased parenteral progestational activity in comparison to progesterone, is non-orally progestationally active and is metabolized androgenic, whereas the corresponding retrosteroid has an increased parenteral progestational activity in relation to retro-progesterone which by itself is The activities which are mentioned above in connection with the compounds of the normal series are reported in the patents in which such compounds are disclosed.

Many additional comparisons based on our own ex- 5 periments will be found in Table I following the examples.

In particular the novel steroids of our invention are the 10a-rnethyl, 9,8-steroids which contain at least 18 carbon atoms in the molecule and wherein any acyclic carbon chain when present and directly attached to the C carbon atom, in the 3 position, contains at least one and not more than five successive carbon atoms.

An important class of these novel steroids of our invention are those in which there is a substituent having a carbon atom directly attached to the C carbon atom which substituent is preferably in the ,8 position, In addi tion it is preferred that the substituent at the carbon atom 14 be in the a position and that the substituent at the carbon atom 8 be in the [3 position.

More particularly the pharmacologically active steroids of our invention are those designated by the following general formula in which the substituents are designated as being in the rx-position by means of a broken line joining the substituent to the steroid nucleus, the substituents are designated as being in the fl-position by means of a solid line joining the substituent to the steroid nucleus and in those cases in which the substituent may be either in the aor fl-position the substituents are indicated as being joined to the steroid nucleus by a broken line and a solid line placed side to side FORMULZ"; I

more progestationally active than progesterone, is orally progestationally active and is non-androgenic even if incorrectly metabolized. 21-acetoXypregna-4,6-diene-3,20- dione of the same patent is Weakly parenteral progestationally active, non-orally progestationally active, produces an increase in the Na/K ratio, has no glycogen storage activity, is not anti-inflammatory and is androgenic, whereas the corresponding retrosteroid is orally and parenterally progestationally active, diuretic with no increase in Na/K ratio, non-androgenic, and is anti-inflammatory. The pregna-1,4,6-triene-3,20-dione has no glycogen storage activity but is parenterally progestationally active but not Orally progestationally active and is metabolized androgenic whereas the corresponding retrosteroid is not progestationally active but induces corpora lutea, is pituitary inhibiting and is non-androgenic even if metabolized incorrectly.

The 3,17,8-diacetoxyandrosta-3,S-diene of the United States Patent 2,885,397 is androgenic, anabolic and is not pituitary inhibiting, whereas the corresponding retrosteroid is non-androgenic, non-anabolic, renotrophic and pituitary inhibiting (we tro wherein 55 R, is a member of the group consisting of carbon to carbon double bonds present at the positions 1, 2, 3 and 4 and n is a whole number from 0 to 2;

R is a member of the group consisting of carbon to carbon double bonds present at the positions 5 and 6 and n is a whole number from 0 to 1;

R is a carbon to carbon double bond present at the position 11 and n is a whole number from 0 to 1;

R is a member of the group consisting of carbon to carbon double bonds present at one of the positions 15,

16 and 17(20), and m is a whole number from 0 to 2',

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, alkyl containing from 1 to 2 carbon atoms, substituted with hydroxy, x0 or both of the same, alkenyl containing from 2 to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hydroxy, acyloxy, alkoxy and aralkoxy groups, the thio analogues of said hydroxy, acyloxy, alkoxy and ara-lkoxy groups, 0X0, ketalized oxo, F, Cl, BI, NI-I2 and wherein each alkyl group contains from 1 to 3 carbon atoms and (2,3-d)-isoxazole, (3,2-c)-pyrazo1e, 2'-methyl-(3,2-d)-thiazole and 2-am.ino-(3,2-d)-pyrimidine heteroyclic groups wherein each of said heterocyclics is for-med by R together with carbon atoms 2 and 3 of the steroid nucleus and R and n is a whole number from 1 to 2;

R, is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, aralkoxy, alkoxy, F, Cl, and Br, and n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, alkoxy, acylthio, aralkoxy, F, C1 and Br, and n is a whole number from 0 to 1;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, methylene, trifluoromethyl, trichloromethyl, tribromomethyl, alkenyl containing from 2 to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hydroxy, acyloxy, alkoxy, aralkoxy, acylthio, oxo, nitro, amino, F, Cl and Br, and n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, alkyl containing 1 to 3 carbon atoms, hydroxy, acyloxy, acylthio, alkoxy, aralkoxy, 0x0, amino, F, C1 and Br, and n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, hy-

droxy, acyloxy, alkoxy and aralkoxy, and

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, alkoxy, aralkoxy, F, C1 and Br, and

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, methylene, alkenyl containing from 2 to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hydroxy, acyloxy, alkoxy, aralkoxy, oxo, amino, F, Cl and Br, and n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy,

aoammn II acyloxy, alkoxy, aralkoxy, 0x0, F, Cl and Br, and m is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, methyl, hydroxymethyl, formyl and together with R the radical wherein the carbon atom of said radical is connected to the carbon atom 13 and the oxygen atom is connected to the carbon atom 11;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, alkoxy and aralkoxy, and

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, alkoxy, aralkoxy, oxo, F, Cl and Br, and n is a Whole number from 1 to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, methylene, trifluoromethyl, trichlorornethyl, tribromomethyl, alkenyl containing from 2 to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hydroxymethylene, hydroxy, acyloxy, alkoxy, aralkoxy, oxo, amino, F, Cl and Br, and 11 is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, hy-

droxy, acyloxy, alkoxy, aralkoxy, thio-analogues of said hydroxy, alkoxy and aralkoxy groups, alkyl containing from 1 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, alkynyl containing from 2 t0 -6 carbon atoms, and said alkyl, alkenyl and alkynyl groups substituted with at least one member of the group consisting of hydroXy-, hydroxy esterified with inorganic acid, hydroxy esterified with inorganic acid of which one of the hydrogen atoms is replaced by an alkali metal atom, acyloXy-, alkoXy-, aralkoXy-, oxo-, amino-, F-, Cl-, Brand the thio-analogues of said hydroxy, alkoxy and aralkoxy groups, and

R is a member of the group consisting of hydrogen, hy-

droxy, acyloxy, alkoxy, aralkoxy, thio-analogues of said hydroxy, alkoxy and aralkoxy groups, P, Cl, Br, alkyl containing from 1-6 carbon atoms, alkenyl containing from 2-6 carbon atoms, alkynyl containing from 26 carbon atoms, said alkyl, alkenyl, and alkynyl groups substituted with at least one member selected from the group consisting of hydroxy-, acyloxy-, a1- koXy-, aralkoxy-, the thio-analogues of said hydroxy, alkoxy and aralkoxy groups, carboxy-, oxo-, amino-, F, Cl and Br, the OX0 group joining R and R the group -CH joining R and R and a spirolactone containing from 36 carbon atoms joining R and R' a ketal group joining R and R and a ketal group RIF] and R16.

An interesitng group of the hormonal retrosteriods of our invention are the 10a-methyl steriods corresponding to the general structural formula:

R is a substituent selected from the group consisting of hydrogen and the methyl radicals, and n is a whole number from -1 to 2;

R is a substituent selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, etherified hydroxy 5 and esterified hydroxy radicals, and n is a whole nurnher from 1 to 2;

R is a substituent selected from the group consisting of keto, hydroxy, esterified hydroxy and etherified hydroxy radicals, and n is a Whole number from 1 to 2;

R is a substituent selected from the group consisting of hydrogen, chlorine and fluorine, and n is a whole number from 1 to 2;

R is a substituent selected from the group consisting of hydrogen, bromine, chlorine, fluorine, hydroxy, methyl, etherified hydroxy and esterified hydroxy radicals, and n is a whole number from 1 to 2;

R is a substituent selected from the group consisting of hydrogen, bromine and fluorine, and

R is a substituent selected from the group consisting of hydrogen, the hydroxy radical and keto radicals, and 11 is a whole number from 1 t 2;

R is a substituent selected from the group consisting of hydrogen, hydroxy, etherified hydroxy, esterified hydroxy and ethyl and methyl radicals, and n is a Whole number from 1 to 12;

R and R q are each selected from the group consisting of hydrogen, aliphatic hydrocarbon radicals containing from 16 carbon atoms, hydroxy derivatives of said aliphatic hydrocarbon radicals, etherified hydroXy derivatives of said aliphatic hydrocarbon radicals, esterified hydroxy derivatives of said aliphatic hydrocarbon radicals and keto derivatives of said aliphatic radicals, and jointly the keto radical with the proviso that at least one of the substituents defined by R and R being a substituent other than hydrogen;

R is a carbon to carbon double bond present at at least one of the positions 1, 2, 3, 4, and n is a Whole number from 0-2.

R is a member of the group consisting of carbon to carbon double bonds present at the positions 5, 6, 7 and 8, and In, is a whole number from 0 to 2;

R is a member of the group consisting of carbon to carbon double bonds present at the positions 8(14) and 9(11), and n is a whole number from 0 to 2;

R is a member of the group consisting of carbon to carbon double bonds present at one of the positions 15 and 16, and n is a Whole number from 0 to 2.

A particular group of compounds of Formula II are those in which there is a conjugated carbon double bond system at the carbon atoms and 7 of the steroid nucleus.

Referring to the general Formula I three particular groups of retrosteroids having female hormonal activity are those in which all substituents are the same as defined therein except that Group A:

R17 iS )CHz and R'17 is H- Group B:

R is OR wherein R is hydrogen, alkyl or acyl, and

R' is OR" wherein R" is acyl.

With respect to the retrosteroids of these formulae having female hormonal activity they have at least one of the following pharmacological activities namely, oral and/or parenteral progestational, anti-progestational,

'uterotrophic, anti-uterotrophic, anti-estrogenic, fertility stimulating, fertility inhibiting, anti-arteriosclerosis, corpora lutea induction, ovulation inhibiting and/or ovulation stimulating activities. In addition some of these compounds may have pituitary stimulating and/or pituitary inhibiting activities.

As to the compounds falling within the groups A, B and C, the introduction of a double bond at the carbon atom number 1 has a tendency to decrease progestational activity and to enhance ovulation stimulating activity. The presence of a keto group at carbon atom number 3 and a double bond at carbon atom 4 has a tendency to enhance oral and parenteral progestational activity as compared with the same activity of the corresponding compound of the invention in which such a keto atom and such a double bond are absent.

The presence of a keto group at carbon atom number 3 and double bonds at carbon atom numbers 4 and 6 has a tendency to enhance oral and parenteral progestational activity and anti-uterotrophic activity as compared with the same activities of the corresponding compound of the invention in which such a keto group and such double bonds are absent. The presence of an alkoxy or acyloxy group at carbon atom number 3 and double bonds at carbon atoms 3 and 5 have a tendency to decrease the intensity of progestational activity but prolong the same as compared with the same activities of the corresponding compound of the invention in which such alkoxy, acyloXy and double bonds are absent. A fluoro or chloro atom at carbon atom number 6 has a tendency to increase any female hormonal activity already possessed by the compound. A double bond at carbon atom number 7 has a tendency to decrease any female hormonal activity already possessed by the compound but to enhance antiarteriosclerotic activity.

Referring to the Formula I three particular groups of retrosteroids having male hormonal activity are those in which all substituents are as defined therein except that I group. Group F:

R is OR wherein R is hydrogen, alkyl oracyl, and R is methyl.

The compounds falling within the above groups D, E and 'F possess at least one of the following pharmacological activities, namely, anti-androgenic, anabolic, renotrophi-c, anti-catabolic, catabolic, increase or decrease of spermatogenesis and/or anti-anemic activities.

In addition some of these compounds may have pituitary stimulating and/or pituitary inhibiting activities.

With regard to the compounds falling within the groups D, E and F the combination of a keto group at the carbon atom number 3 with a double bond at carbon atom number 4, has a tendency to enhance anabolic and/or renotrophic activities. The combination of a keto group at carbon atom number 3 with double bonds at carbon atoms 4 and 6 in the compounds'falling within the groups D, E and F tends to impart anti-androgenic and/or pituitary inhibiting activities. A halogen atom especially a fluorine or chlorine atom at the carbon atom number 6 in compounds falling within the groups D-F has a tendency to increase the anabolic activity.

R is hydrogen or acyl, R is an olefinic double bond at the carbon atom 6 and n =1 and R is alkyl of l-6 carbon atoms, alkenyl of 2-6 carbon atoms or alkynyl of 2-6 carbon atoms.

The following structural Formula G represents compounds having progestational, deciduomata inducing and fertility inhibiting activities:

G CH CH a a f E '17 i H /i wherein:

R is a 3-kcto-A system, a A -enolether system or a A -enolester system;

R is a hydrogen, fiuoro or chloro atom; in a, [3 or planar position;

R is a double bond between the carbon atoms 6 and 7,

when R is a 3-keto-A -system, and n is a whole number from 0 to 1;

R is a hydroxy group, alkoxy, aralkoxy or an acyloxy group; and

R' is an alkenyl group containing from 3-6 carbon atoms.

In particular the group R may represent one of the following groups:

iii

1G The following structural Formula H represents conipounds having at least anabolic activity.

E (Rb) Ilb e) a wherein R is hydrogen or acyl, R is hydrogen, fluorine or chlorine, n =12, R is an olefinic double bond at the carbon atom 6, n =Ol, and when 11 :2, R comprises one hydrogen radical and one halogen radical.

The following structural Formulae I and I represent compounds having at least anti-androgenic activity.

CO CH:

wherein R is an olefinic double bond at the carbon atom 6 and n =O-1 and R37 is a member of the group consisting of alkenyl of 36 carbon atoms and alkynyl of 2-6 carbon atoms.

wherein R is a member of the group consisting of H, acyls of aliphatic monocarboxylic acids containing from 1-6 carbon atoms, acyls of aliphatic dicarboxylic acids of 3-6 carbon atoms and acyls of monoalkali metal salts of dicarboxylic acids.

Among the representative retrosteroids of our invention are the following:

l-dehydro-2-methyl-retro-testosterone-( l3 l-dehydro-2-methyl-retro-testosterone 17-acylate-( l3 4-rnethyl-retro-testosterone 3-enolacylate of 4-rnethyl-retro-testosterone 17-acylate 4-methyl-6-dehydro-retro-testosterone 4-methyl-6-dehydro-retro-testosterone 17-acylate 4-chloro-retro-testosterone 4-chloro-retro-testosterone l7-acylate 4-bromo-retro-testosterone 4-hydroxy-retro-testosterone 4-hydroxy-6-dehydro-retro-testosterone ZB-fluoro-retro-testosterone-( l6) 3-enolacylate of 2,8-fluoro-retro-testosterone 17-acylate l-dehydro-2-fiuoro-retro-testosterone-( 16) 1-dehydro-2-fiuoro-retro-testosterone l7-acylate 1,6-bisdehydro-2-fluoro-retro-testosterone-(4,16) 1,6-bisdehydro-2-fluoro-retro-testosterone l7-acylate Zfl-hydroxy-retro-testosterone retro-Sfl-androstan-17;8-ol-2,3-dione enolacylate of retro-Sfi-androstan-l7B-ol-2,3-dione l7- acylate 17 carbon atoms but not more than three carbon atoms together withQ when Q is alkyl.

Another group of these novel intermediates in those which also have the same structure as Formula I in respect to all the substituents except that n is a whole number from to 2 and R together with R' is the group wherein X is the carbon atom 17 of the nucleus.

Other novel intermediates are those similar to the above two groups and Formula I but in which there are present a double bond at 8(9) or 9(11) and/or one or more epoxy groups joining the following pairs of nuclear carbon atoms: 1,2; 4,5; 5,6; 6,7; 9,11; 11,12; 14,15 and 16,17.

The use of these novel steroids of our invention in the preparation of our novel hormonally active retrosteroids will be apparent from the description of the methods of preparing these retrosteroids which follows:

We may start with steroids already containing the ccmethyl 9,8-configuration such as lumisterol 2 or lumisterol 3.

Also the 100: methyl, 9,8-configuration of the retrosteroids of our-invention may be prepared by irradiation with ultraviolet light of certain normal steroids having a A configuration in the same manner that ergosterol and 7-dehydrocholesterol are converted into lumisterol 2 and lumisterol 3, respectively.

Thus, irradiation (preferably with ultraviolet light) of 5,7 bisdehydro-normal steroids, having the 10 methyl group in 5 position, a hydrogen atom at carbon atom 9 in a position, a substituent at carbon atom 13 in 3 position and a substituent at carbon atom 14 in on position, followed by eliminations of the double bond between carbon atoms 7 and 8 produces steroids having a nucleus of which the configuration at the carbon atoms 10, 9, 8, 13 and 14 is that of the nucleus ofour novel retrosteroids (lOu-methyl, 9,8, 13B, 140:).

In this manner, they lOa-methyl, 9;8-configuration in the novel steroids of our invention, can be introduced as set out in the foregoing paragraph. The starting materials used in the irradiation process may already contain the substituents as set out inFormula I. However, sometimes the presence of certain light. absorbing chemical systems other than the 5,7-bisdehydro system may disturb the conversion into our novel lOa-methyl, 9B-steroids.

In principle this method of introducing the Illa-methyl, 9fi-configuration by irradiation with. ultraviolet light may be applied to all normal steroids (those containing a 10,8- methyl, 9aconfiguration) with two limitations. One of these limitations is that there be no substituent present providing steric hindrance of the IO-methyl group. It is particularly important that the substituents present on the- 1,9 or 11 positions of the steroid molecule do not stericly hinder the IO-methyl group. Also there must be no substituents whichhave a natural absorption between 220 and 330m or materially influence the absorption of the (A -system. Thus no non-ketalized keto group or one or more double bonds in conjugation with the A -system may be present.

Starting products for the preparation of the retrosteroids according to the invention may be, for example, those natural sterols which have a saturated or unsaturated aliphatic carbon chain, such for example ergosterol.

Alternatively, the starting products may be found in the classes of. the sapogenines, which have a heterocyclic group in the side chain,,for example, diosgenine. In both cases the M -system should be provided for-the radiation if it is not already present in the molecule.

The introduction of the IOa-methyl, 9B-configuration may be the first step to be carried out as in the following general method:

(a) Introduction of the retro-structure into steroids of the normal series by irradiation of suitable A -steroids (b) Introduction of substituents into retrosteroids (c) A series of reactions to obtain a desired grouping at carbon atom 17, starting from retrosteroids with an aliphatic side chain of 6-10 carbon atoms at carbon atom 17 The sequence of the processes as described maybe varied. For example, starting from a retrosteroid which has been prepared beforehand, for example dihydroisolumisterone the side chain degradation and introduction of the desired substituents may be carried out entirely or partially in the inverted sequence. 2 fluororetro-progesterone may be prepared for example by introducing a fluorine atom in the 2-position in retroprogesterone or by side chain degradation of 2-fluorodihydroisolumisterone.

It is also possible to carry out the irradiation with steroids of the normal series, in which all of the desired substituents have been introduced, or after entire or partial side chain degradation for example with 16-methylpregna-5, 7-diene-3B-oLZO-one.

The sequence of the processes which is chosen can be decided separately for the product and starting materials employed.

Changes in the nuclear structure other than the introduction of the 10a-methyl, 9,8-configuration may be carried out as follows:

14B-steroids may be prepared by hydrogenation of 14(15) unsaturated steroids, for instance with hydrogen and using palladium as a catalyst. Thus pregna-5,l4,l6- trien-3fi-ol-20-one when hydrogenated yields 145,17B pregna-5-en-35-01-20-one. (Fieser and Fieser, Steroids, 1959, page 567).

13oL-SI6I'OldS may be prepared by irradiation of 17-keto steroids with ultraviolet light according to Fieser and Fieser, Steroids, 1959, page 520. Thus irradiation of 3a-hydroxy-5m-androstan-17-one yields 30: hydroxy 5oz, 13a-androstan-l7-one.

Set-steroids may be prepared by hydrogenation of 11- keto-21 steroids in the presence of a catalyst (Tetrahedron 1, 22 (1957)). Thus 3 8-hydroxy-1l-oxo-androst- B(9)-ene may be hydrogenated in the presence of palladium to produce 3fi-hydroxy-1l-oxo-8u-androstane.

l8-nor steroids may be prepared by reacting 18hydroxy- 17-keto steroids with sodium hydroxide (Fieser and Fieser, Steroids, 1959, page 470). Thus by reacting 3B,18-di hydroxy-audrost-S-en-17-one with sodium hydroxide will be produced 3B-hydroxy-18-nor-androst-5-en-17-one.

The expressions: inorganic acid, acyl, acyloxy, alkoxy, aralkoxy, acylthio, ketol and ketalized oxo, whenever used in this application, have the following meanings.

Inorganic acid is one of the following inorganic acids: phosphoric acid, sulphuric acid, nitric acid, nitrous acid, boric acid.

Acyl or acyloxy are the acyl or the acyloxy groups respectively of the following acids:

(a) Saturated or unsaturated, branched or unbranched, cyclic or non-cyclic aliphatic monoor dicarboxylic acids having 12O carbon atoms wherein the aliphatic part of the molecule may be substituted by one or more halogen atoms, amino groups, sulphonic acid groups.

(b) Phenylalkyl monoor dicarboxylic acids of which the phenyl part of the molecule may besubstituted with alkyl groups containing 13 carbon atoms, sulphonic acid groups, alkoxy groups of which the alkyl group is branched or unbranched and contains 1-10 carbon atoms and acids of which the alkyl part of the phenyl alkyl monoor dicarboxylic acid contains from 0.6 carbon atoms and is branched or unbranched, saturated or unsaturated, Of these acids the following specific examples may be given: formic acid, acetic acid, acroleic acid, isobutyric acid, palmitic acid, cyclohexane-monocarboxylic acid, trichloroacetic acid, aminoacetic acid, oxalic acid, malonic acid,

maleic acid, benzoic acid, terephthalic acid, p-ethyl benzoic acid, benzene sulphonic acid, m-ethoxy benzoic acid, phenyl acetic acid, and cinnamic acid.

Alkoxy is the alkoxy group of mono or di-aliphatic alcohol of which the alkyl group contains from 1-20 carbon atoms and which may be branched or unbranched, cyclic or non cyclic, saturated or non saturated and which alkyl group may be substituted with halogen or alkoxy, whereby this latter alkoxy substituent may be attached to the same carbon atom of the steroid nucleus as the main alkoxy group. Of these alcohols the following examples may be given: methanol, ethanol, propanol-Z, 2- chloroethanol-l, 2-ethoxyethanol-1 and glycol.

Aralkoxy is the aralkoxy group of a mixed aromatic aliphatic alcohol in which the hydroxyl group is attached to the aliphatic part of the molecule and of which the alkyl (ene) group contains from -6 carbon atoms which may be branched or unbranched. Of these alcohols the following examples may be given: benzyl alcohol and phenol.

Acylthio is the acylthio group of acyl thiols. In acylthio the expression acy has the meaning as given hereabove.

A ketal is the dihydroxy steroid ketal of an aliphatic aldehyde, aliphatic ketone, mixed aliphatic aromatic aldehyde, mixed aliphatic aromatic ketone, or a diaromatic ketone.

Ketalized oxo is the ketalized oxo group resulting from the reaction between two molecules of a monohydroxy aliphatic alcohol containing from 1 to 6 carbon atoms and one molecule of an oxo group containing 10a,9;3-methyl steroid, or resulting from the reaction between one molecule of a dihydroxy aliphatic alcohol containing from 1 to 6 carbon atoms and one molecule of an oxo group containing IOa-methyl 9f3-steroid.

The introduction of alkyl substituents may be carried out as follows:

1) By the reaction of keto, conjugate ketoand doubly conjugate keto-steroids with alkylation agents, such as, for example, Grignard reagents, alkyl-alkali-metal compounds or an alkyl halide, in the presence of an alkali metal alkoxide.

For example, according to the method described by Zderic et al. (J. Am. Chem. Soc. 82, 3404 (1960)), 11- keto-retrosteroids lithium give the corresponding 11- methyl-ll-hydroxy steroids. In this manner, ll-kcto-retroprogresterone 3,20-bisethylene ketal may be converted to the corresponding 11-methyl-1 l-hydroxy compound. After acid hydrolysis, this provides 1l-methyl-ll-hydroxy-retroprogesterone.

Further, 11-keto-retro-testosterone 3-ethylene ketal may be converted into the corresponding ll-methyl-l l-hydroxy compound. After acid hydrolysis, this yields the ll-methyl- 1 1-hydroxy-retro-testosterone.

The reaction of 6-keto-retro-steroids with methyl magnesium halides gives the 6-methyl-6-hydroxy steroids, for example by the method described by Fieser et al, (J. Am. Chem. Soc. 73, 4660 (1951)). In this manner, 6-ketoretro-pregnane-3-ol-20-one 20-ethylene ketal may be converted into 6-methyl-3,6-dihydroxy-retro-pregnane-20-one 20-ethylene ketal. Further, 6-ket0-retro-androstane-3,17-diol may be converted into 3,6,17-trihydroxy-6-methyl-retro-androstane. The reaction of 3-keto-retrosteroids with methyliodide in the presence of potassium-t-butoxide by the procedure of Ringold et al. (J. Am. Chem. Soc. 81, 427 (1959)), provides the corresponding 2,2-dimethyl steroids. In this manner, 2,2-dimethyl-retro-pregnane-3,20-dione 20-ethylene ketal may be produced from retro-pregnane-3,20-dione 20-ethylene ketal.

Further, 2,2-dimethyl-retro-androstane-175 ol 3 one may be produced from retro-androstane-17 8-01-3-one.

Addition of methyl Grignard reagents to A -ket -retropregnanes according to the method described by Bernstein et al. (J. Org. Chem., 26, 269 (1961)), provides 16- methyl compounds. Thus, 3,8-hydroxy-16-methyl-retropregn-5-en-20-one may be produced from 3fi-acetoxyretro-pregna-S,16-diene-20-one.

Conversion of 3-keto-A -retrosteroids with methyl halides in the presence of potassium-t-butoxide by the procedure of Woodward et al. (I. Am. Chem. Soc. 76, 2852 (1954)), gives 3-keto-4,4-dimethyl-A -steroids. For example, such a reaction with bismethylene-dioxy-retrohydrocortisone gives the 4,4-dimethyl-17(20),20-bismethylenedioxy-retro-pregn-5-ene-3,ZO-dione.

Further, with retro-testosterone, such a reaction gives the 4,4-dimethyl-retro-androst-S-ene-17fl-ol-3-one.

(2) By the addition of diazomethane to double bonds, succeeded by pyrolysis or cleavage under acid conditions of the pyrazolines, if required with subsequent hydrogenation of the compounds obtained. According to the procedure of Wiechert and Kaspar Chem. Ber. 93, 1710 (1960)), A -3-keto-retrosteroids react with diazomethane with the formation of pyrazolines, from which the 1,2-methylene-A -3-keto-steroids are produced by pyrolysis. Under the action of, for example, acid alumina, however, the pyrazolines are converted into the AH- methyl steroids. For example, 17a-acetoxy-1,2-methyleneretro-pregna 4,6 diene-3,20-dione and 17u-acetoxy-1- methyl-retro-pregna-1,4,6-triene-3,20-dione may be produced from 17a-acetoxy-retro-pregna-1,4,6-triene-3,20- dione.

Further, 1,Z-methylene-retro-androsta-4,6-diene-1718-01- 3-one 17-acetate and 1-methyl-retro-androsta-1,4,6-trienel7fi-ol-3-one 17-acetate may be produced from retroandrosta-1,4,6-triene-17B-ol-3-one 17-acetate.

(3) By the reaction of a methylene group activated by a keto-group, with a mono-or dica rboxylic acid ester,

R- Oalkyl where R may be H or succeeded by a reaction with an alkyl halide with subsequent splitting ofl? of the carboxylic acid group.

For example, 3-ketoA -retrosteroids when reacted with diethyloxalate in the presence of sodium hydride according to the method described by Ringold et al. (J. Am. Chem. Soc. 81, 427 (1959)), after reaction with a methyl halide followed by a reaction with an alkali-alkoxide give the 2-methyl-3-keto-A -retrosteroids. Thus, from retropregn-4-ene-20-ol-3-one ZO-acetate the Z-methyl-retropregn-4-ene-20-ol-3-one 20-acetate may be produced.

Further, in this manner 2-methyl-retro-testosterone may be produced from retro-testosterone.

(4) By the reaction of retrosteroid epoxides with, for example, alkyl Grignard reagents. For example, 3-cyclo ethylenedioxy 5(6) epoxy-retrosteroids after reaction with methyl magnesium halides according to the method described by Babcock et al. (I. Am. Chem. Soc. 80, 2904 (1958)), give the 6-methyl-5-hydroxy compounds, from which after hydrolysis and dehydration the 6-methyl-3- keto-A -retrosteroids can be produced. Such a reaction with, for example, '5,6-epoxy-17 -hydroxy-retro-pregnane- 3,20-dione bisethylene acetal gives the corresponding 5- hydroxy-6-methyl compound which, after hydrolysis and subsequent dehydration, provides the 6-methyl-17a-hydroxy-retro-progesterone.

Further, from 5,6-epoxy-retro-androstaner3,17-dio1 may be obtalned in this manner 5-hydroxy-6-methyl-retroandrostane-3,17-diol.

The introduction of double bonds in retrosteroids may be effected by the following methods:

1) By microbiological dehydrogenation, as described, for example, for the production of 1-dehydro-steroids by 21 Sih et al. (I. Am. Chem. Soc. 82, 2653 (1960)). In this manner, retro-progesterone may be converted into 1- dehydro-retro-progesterone, or, retro-testosterone may be converted into 1-dehydro-retro-testosterone.

(2) By the direct dehydrogenation of saturated or non-saturated steroid ketones and of unsaturated steroids with, for example, mercury acetate, iodine pentoxide, selenium dioxide, manganese dioxide, substituted quinones such as chloranil and dichlorodicyanobenzoquinone, for example by the methods of Heilbron et al. (J. Chem. Soc. 1935, 1221), Burn et al. (Proc. Chem. Soc. 1960, 14), Agnello et al. (I. Am. Chem. Soc., 82, 4293 1960)), and Sondheimer et al. (I. Am. Chem. Soc., 75, 5932 (1953)). In this manner, 6-dehydro-retro-progesterone may be produced from retro-progesterone and 1,6 bisdehydro 1Macetoxy-retro-progesterone may be produced from 6-dehydro-17a-acetoxy-retroprogesterone. 3,17 diacetoxy retro-androsta-5,7,9(1l)-triene may be obtained from 3,17 diacetoxy retro-androsta-5,7-diene, and 1-dehydro-retro-testosterone may be obtained from retro-testosterone.

(3) By the splitting oil of substituents, for example, dehydrohalogenation of halogenated retro-steroids, for example with an organic base, has been described by Djerassi et al. (I. Am. Chem. Soc. 72, 4534 (1950)), for the production of 6-dehydrofrom 6-halo steroids. In this manner, 6 dehydro-retro-progesterone may be produced from 6-brorno-re=tro-progesterone. Further, 6-dehydroretro-testosterone 17-acetate may be produced from 6 bromo-retro-testosterone l7-acetate.

Another example of splitting off is the dehydration of hydroxylated retro-steroids, for example under the influence of phosphorus-oxychloride and an organic base, from methane sulphonyl chloride or from methyl chlorosulphite, for example by the methods described by Chamberlin et al. (J. Org. Chem. 25, 295 (1960)). In this manner, retro-hydrocortisone acetate may be converted into 170:,21-dihydroxy-retro-pregna-4,9(1l)-diene- 3,20-dione 21-acetate. Further, 1l-hydroxy-retro-androst- 4-ene-3,20-dione may be converted into retro-androsta- 4,9(11)-diene-3,20-dione.

The introduction of hydroxy groups into retro-steroids may be effected as follows:

(1) By microbiological hydroxylation, for example as described by Peterson et al. (J. Am. Chem. Soc., 74, 1871 (1952)). In this manner, 11,17u,2l-trihydroxyretro-pregn-4-ene-3,ZO-dione may be produced by microbiological hydroxylation of 170:,2l-dihydroxy-retro-pregn- 4-ene-3,20-dione. Further, 11-hydroxy-retro-testosterone may be produced by microbiological hydroxylation of retro-testosterone according to the same method.

(2) By cleavage of epoxy-retrosteroids. This may be effected by means of reducing agents, such as, for example, alkali-bariumand alkali-aluminum-hydride, chromium salts, and by catalytic hydration. According to the method described by Cole et al. (J. Org. Chem. 19, 131 (1954)), the 16-hydroxy compounds may be produced from 16,17-epoxy-retrosterids. Thus, 16,17- epoxy-retro-pregn-4-ene-21-ol-3,20-dione yields the retropregn 4 ene-16,21-diol-3,20-dione. Further 3,17-dihydroxy- (6)-epoxy-retro-androstane may be converted into 3,6,17-trihydroxy-retro-androstane.

Cleavage of epoxy-retrosteroids may also be performed by means of hydro halogenic acids, for example as described by Ringold et al. (I. Am. Chem. Soc. 78, 816 (1956)), for the production of 17a-hydroxy-pregnanes from 16,17-epoxy-pregnanes. According to this method, l6,17-epoxy-retro-progesterone, after reaction with hydrogen bromide succeeded by reductive debrornination, yields the l7u-hydroxy-retro-progesteronc. Further, 9- 1 1 -epoxy-retro-androst-4-ene-l7 3-ol-3-one with hydrogen fluoride yields 11-hydroxy-9-fluoro-retro-testosterone.

(3) By hydroxylation of double bonds, for example with asmium tetroxide. For example, osmate esters, produced by oxidation of alkenes with osmium tetroxide,

22 are split up into the diols, employing the procedure of Baran (J. Org. Chem. 25, 257 (1960)). In this manner, 3-hydroxy-retro-pregn-5-ene-20-one may be converted into 3,5,6-trihydroxy-retro-pregnane-ZO-one. Further, 31ihydroxy-retro-androst-5-ene-17-one may be converted into 3,3,5,6-trihydroxy-retro-androstane-17-one.

(4) By the reaction of enol ethers or enol esters with organic peracids. If, for example, A -3-enol acylates are reacted with per-acids, employing the methods of Romo et al. (J. Org. Chem. 19, 1509 (1954)), the 3-keto-A -6 hydroxy steroids are produced. Thus, 3-acetoxy-retropregna-3,5-diene-20-one with monoperp'hthalic acid yields the 6 hydroxy retro progesterone. Further, 3,17,3-diacetoxy retro androsta-3,5-diene with monoperphthalic acid yields the 6-dehydro-retro-testosterone 17-acetate.

(5) By the hydrolysis or acyloysis of halo-steroids, for examplewith an alkali salt of a carb xylic acid by the method of Ruschig (Ber. 88, 878 (1955)), 21-iodosteroids being converted with potassium acetate into the 21-acetoxy compounds. Hydrolysis of these compounds, for example according to Robinson (J. Am. Chem. Soc. 82, 4611 (1960) with perchloric acid yields the free 21- hydroxy compounds. The hydrolyses may suitably be performed with a solution of potassium bicarbonate in aqueous methanol. Thus, 2l-iodo-retro-progesterone may be converted into 2l-acetoxy-retroprogesterone, which again may be converted by hydrolysis into 21-hydroxyretro-progesterone. Further, in this reaction 6-bromoretro-testosterone 17-acetate gives 2-acetoxy-retro-testosterone 17-acetate', from which, after hydrolysis, 2- hydroxy-retro-testosterone is obtained.-

(6) By reduction of keto-steroids, for example with lithium aluminum hydride by the method described by Sondheimer et al. (J. Am. Chem. Soc. 75, 5930, 5932 (1953)). In this manner, retro-progesterone may be reduced to retro-pregn-4-ene-diol. Further, for example, retro-androst-4-ene-3,17-dione may be reduced to retroandrost-4-ene-3,17-diol.

(7) By hydrolysis of esters or ethers, for example by the method of Dory et al. (CA. 53, 17181 (1955)), with sodium methylate in methanol. The saponification may also be performed with dilute'inorganic acids, dilute inorganic bases, sodium carbonate and sodium bicarbonate. Thus, hydrolysis of 17a,21-dihydroxy-retro-progesterone ZI-acetate with sodium bicarbonate in dilute diox ane gives the 17a,21-dihydroxy-retro-progesterone. Further, the hydrolysis of retro-testosterone l7-acetate gives retrotestosterone.

The introduction of acyloxy groups into the retrosteroid series may be carried out as follows:

(1) By acylolysis of halo-retrosteroids as described hereinbefore.

(2) By the reaction of hydroxyand keto-retrosteroids with acids, acid anhydrides or acid chlorides in the presence of, for example, a catalyst (for example, pt-oluene sulphonic acid, pyridine-HCI) or acid binding reagents (for example organic bases) or water-binding reagents (such as, for example, trifluoroacetic acid anhydride). For example, 17a-ethyl-retro-testosterone may be esterified with the acid chloride of B-phenyl-propionate in pyridine by the method of Gould et al. (J. Am. Chem. Soc. 79, 4472 (1957), to form l7-(fi-phenyl propionate) ester of 17a-ethyl-retro-testosterone. Further, retro-androst-4-ene-175-ol-3-one l7-(,8-pheny1 propionate) may be obtained by esterification of retro-testosterone with the acid chloride of ,B-phenyl propionic acid in pyridine.

The introduction of alkoxy and arylkoxy groups into the 10a-methyl 9,8-steroid series may be carried out as follows:

(1) By the reaction of keto-retrosteroids with a suitable hydroxy compound (mono or poly), for example, in the presence of a catalyst, such as, for example, hydrochloric acid, pyridine-hydrochloric acid and p-toluene sulphonic acid, employing the method described by Ercoli et al. (I. Am. Chem; Soc. 82, 746 (1960)). In this manner, the cyclopentyl enolether of 17a-acetoxy-retroprogesterone may be produced. Another example is the production of the 3-enol 'benzyl ether of 6-dehydro-retroprogesterone by the action of benzyl alcohol and hydrochloric acid on 6-dehydro-retro-progesterone. Further, the cyclopentyl enol ether of retro-testosterone may be produced in this manner from retro-testosterone and cyclopentanol.

(2) By an acid-catalysed interchange reaction between the chosen hydroxy compound and preformed enol ether, for example by the method of 'Ercoli et al. (J. Am. Chem. Soc. 82, 746 (1960)). In this manner, 3-enol ethyl ether of retro-progesterone may be converted into 3-enol benzyl ether, or, 3-enol ethyl ether of retrotestosterone may be converted into 3-enol benzyl ether.

(3) By the reaction of keto-retrosteroids with trialkyl orthoformates with the use of an acid catalyst, for example an ethanolic hydrogen chloride solution, for example -by the method of Ruyle et al. (J. Org. Chem. 25, 1260 (1960)). In this manner, l7ot-[2-methallyl]-retrotestosterone may be converted into 3-ethoxy-17a-[2'- methallyl] -retro-androsta-3,5-diene-17fi-ol, or retro-testosterone may be converted into 3-ethoxy-retro-androsta-3,5- diene-17B-ol.

(4) By the reaction of a hydroxy-retrosteroid with an alcohol in the presence of a catalyst, such as, for example, an inorganic acid or p-toluene sulphonic acid, for example by the method of Sondheimer et al. (Tetrahedron 5, 15 (1959)). In this manner, 3-methoxy-retro-pregn-4- ene-20-one, may be produced from S-hydroxy-retropregn-4-ene-20-one, 3 methoxy-retro-androst-4-ene175- 01 from 3,17 9-dihydroxy-retro-androst-4-ene, 3-methoxyretro-.pregn-4-ene-20-one from 3 -hydroxy-retro-pregn-4-' ene-ZO-One, and 3 methoxy retro androst-4-ene-17/3-ol from 3,1713-dihydroxy-retro-androst-4-ene.

(5) By the reaction of a hydroxy-retrosteroid with diazomethane in the presence of a catalytic amount of fluoboric acid by the method of Neeman et al. (Tetrahedron 6, 36 (1959)). Thus, 3-methoxy-retro-pregn-4-ene- 20-one is obtained from retro-pregn-4-ene-3-ol-20-one. Further, 3-hydroxy-retro-androst-4ene-17-one may be converted into 3-methoxy-retro-androst-4-ene-17-one.

T he production of halo-retrosteroids may be carried out as follows:

(1) By the addition of halogen to double bonds in retro-steroids, for example by addition of chlorine to 3- hydroxyA -retrosteroids or addition of mixed halogens, such as BrF and JF, to M -retrosteroids according to Bowers et al. (J. Am. Chem. Soc. 82, 4001 (1960)). 'By this method, 17a,21-dihydroxy-retro-pregna-4,9-(11 -diene-3,20-dione al-acetate may be converted into the 9,11- dihalo compounds. Thus, for example, 9(11)-dehydroretro-testosterone may be converted into 9,11-dihaloretro-testosterone.

(2) By the substitution-halogenation at an allyl position adjacent to a double bond or of a methylene group adjacent to a keto group in retrosteroids, for example with bromine, N-bromo-succinimide, dibromo-dimethylhydantoin etc., for example by the method of Djerassi et al. (L-Am. Chem. Soc. 72, 4534 (1950)) for the production of 6 halo 3keto-A -steroids from 3-keto-A steroids. Thus, retro-progesterone 20-cycloethylene ketal may be brominated to form the 6-bromo compound and retro-testosterone 17-acetate may be converted into 6 bromo-retro-testosterone 17-acetate. Furthermore, retropregn-5-ene-3B-ol-20-one 3-acetate may be converted into 17a bromo-retro-pregn-S-ene-3B-ol-20-one 3-actate, the double bond being protected during the reaction by conversion of the dibromide by the method of Engel et al. (Can. J. Biochem. Physiol. 35, 1047 (1957), and Can. J. Chem. 38, 452 (1960)).

(3) By the reaction of enol esters, enol ethers and enamines with halogenating agents, such as, for example, halogen, N-halo-imides, perchlorylfluoride, Br-F. In this manner, 3-enol esters of 3-keto-A -retrosteroids may be converted with perchlorylfluoride according to the method of Bloom et al. (Chem. a. Ind. 1959, 1317) into the 3- keto-A -6-fluoro-retrosteroids. By this method, the 3-enol acetate of retro-progesterone may be converted into 6aand 6B-fluoro-retro-progesterone, and 3-enol acetate of retro-testosterone 17-acetate may be converted into 60cand 6,6-fluoro-retro-tetosterone 17-acetate.

Furthermore, the 3-enol ethers of 3-keto-A -retrosteroids may be converted with N-halo-imides by the method of Ringold et al. (J. Am. Chem. Soc. 81, 3485 (1959)) into the 6-halo-3-keto-A -retrosteroids. Thus, reaction of 3-ethyl enol ether of 17a-acetoxy-retro-progesterone with N-chlorosuccinimide gives 6-Chl0IO-170cacetoxy-retro-progesterone. Further, reaction of 3-enol ethyl ether of retro-androst-4-ene-3,17-dione with N- chlorosuccinimide yields 6-chloro-retro-androst-4-ene-3, 17-dione.

Furthermore, the enamines of 3-keto-A -retrosteroids may be converted by a reaction with perchlorylfluoride followed by isomerisation with, for example, hydrochloric acid by the method of Joly et al. (Bull. 1961, 569) into 3-keto-4-fluoro-A -retrosteroids. Thus, the 3-pyrrolidyl-A -enamine of 17a-acetoxy retro-progesterone yields the 4-fluoro-17a-acetoxy-retro-progesterone, and 3-pyrrolidyl-A -enamine of retro-testosterone yields 4-fluoro-retro-testosterone.

(4) By the reaction of retrosteroids of the following type: retrosteroid where R is an alkyl group and R may be H or where R' may be an alkyl group, which may be obtained by condensation of a methylene group activated by a keto-group with a mono-or dicarboxylic acid ester (for example ethylformate, diethyloxalate), with halogenating agents, such as halogen and perchlorylfluoride, with subsequent splitting off of the carboxylic acid group. Thus, according to the method of Kissman et al. (J. Am. Chem. Soc., 82, 2316 (1960)), the sodium salt of 21-ethoxallyl-retro-progesterone may be converted with perchlorylfluoride and subsequent treatment with potassium acetate into 21-fluor0-retro-progesterone. Substitution of bromine for the perchlorylfluoride gives 21-bromo-retro-progesterone. Further, according to the method of Edwards et al. (J. Am. Chem. Soc., 81, 5262 (1960)), Z-fluoro-retro-testosterone may be produced from the sodium salt of 2-hydroxymethylene-retro-testosterone by reaction with perchlorylfluoride and subsequent treatment with potassium acetate.

(5) By cleavage of epoxides, for example with hydrohalogenic acids or BF for example by the method of Romo et al. (J. Org. Chem. 21, 902 (1956)), according to which 16(17)-epoxides are treated with HBr. Thus, 16(17)-epoxy-retro-progesterone may be converted into 16-bromo-17a-hydroxy-progesterone. According to the method of Bowers et al. (Tetrahedron 3, 14 (1958)),

' 6-fluoro-3,17-diacetoxy-retro-androstane-5-ol may be produced from 3,17-diacetoxy-5 (6)-ep0Xy-retro-androstane.

The introduction of oxo-groups in retrosteroids may be carried out as follows:

(1) By oxidation of hydroxy-retrosteroids, for example according to Oppenauer as described for the normal series by Shepherd et al. (I. Am. Chem. Soc. 77, 1212 (1955)). By this method, retro-pregn-5-ene-3-ol-20-one may be converted into retro-progesterone, or retroandrost-5-ene-3-ol-17-one may be converted into retroandrost-4-ene3,17-dione. The'oxidation may also be performed with chromic acid, for example in pyridine, by the method of Sondheimer et a1. (Tetrahedron 5, 15 (1959)). Thus, 20-hydroxy-retro-pregn-4-ene-3-one may be converted into retro-progesterone. Further, from retrotestosterone will be obtained androst-4-ene-3,17-dione. The oxidation of hydroxy-groups occupying an allyl position with respect to a double bond, may suitably be performed with manganese dioxide, for example by the method of Sondheimer et al. (J. Am. Chem. Soc. 75, 5930 (1953)), and with quinones, such as, for example, dichloro-dicyanobenzoquinone as described by Burn et a1. (Tetrahedron Letters 9, 14 (1960)). Thus, retro-pregn- 4-ene-3,20-di01 may be converted into ZO-hydroxy-retropregn-4-ene-3-one, and according to these two manners, retro-androst-4-ene-3,17/3-diol may be converted into retro-testosterone.

(2) By oxidation of A double bonds for example by ozonisation with the formation of 17-ketones, employing the method of Pederson et al. (I. Am. Chem. Soc. 79, 115 (1957). Thus, ozonisation of the 22-cyanohydrin of retro-bisnorchola-4,17(20)-diene-3-on-22-al gives the retro-androst-4-ene-3,17-dione.

(3) By hydrolysis of enol esters or enol ethers of retrosteroids, for example by acid hydrolysis as described by Serini et al. (Ber. 71, 1766 (1938)). Thus, 3-ethoxyretropregn-3,5-diene-20-one may be hydrolysed to retro progesterone. Further, 3-ethoxy-retro-androstat-3,S-diene- 17-one may be hydrolysed to retro-androst-4-ene-3,17- dione.

(4) By the microbiological oxidation of hydroxy-retrosteroids, for example as described by Perlman (Science 115, 529' (1952). Thus retro-pregn-4-ene-3-ol-20-one may be converted into retro-progesterone, or 17-acetoxy-retroandrost-5-ene-3-ol, may be converted into retro-testosterone 17-acetate. The production of acylthio-retrosteroids may be effected by the method of Dodson et al. (J. Am. Chem. Soc. 81, 1224 (1959)), for example for the introduction of 1- and 7-acylthio groups. Thus, 6-dehydro-retro-progesterone after reaction with ethanethiolic acid gives 7-acetylthio-retro-progesterone. Further, 6-dehydro-retro-testosterone after reaction with ethanethiolic acid yields the 7-acetylthio-retro-testosterone.

The production of amino-retro-steroids may be effected by reduction of retrosteroid-oximes, for example with LiA1H as described by Shoppee et al. (J. Chem. Soc. 1956, 1649). Thus, the dioxime of 6-dehydro-retroprogesterone yields 3,20-diamino-retro-pregna-4,6-diene. Further, the oxime of retro-testosterone with LiAlH in ether yields the 3-amino-retro-androst-4-ene-175-01.

The production of monoalkyland dialkyl-substituted amino u-methyl, 9fi-steroids may be efiected by reacting aminoor monoalkyl substituted amino loot-methyl, 9B-steroids with alkyl halides, for example with an alkyl bromide. Thus 3-amino-retro-androstan-17,8-01 when reacted with methyl bromide yields 3-(N-methylamino)- retro-androstan-17fl-ol.

The production of retrosteroid-[2,3-d]-isoxazoles may be performed by the method of Clinton et al. (J. Org. Chem. 26, 279 1961)), by reacting 3-keto-2-hydroxymethylene retrosteroids with hydroxylamine hydrochloride. Thus, 2-hydroxymethy1ene-17a-allyl-retro-testosterone may be converted into 17-hydroxy 17a-allyl-retroandrost 4-eno-[-2,3-d]-isoxazole. Further, 2 hydroxymethylene-retro-testosterone may be converted into 1718- hydroxy-retro-androst-4-eno- [2,3-d] -isoxazole.

The production of retrosteroid-[3,2-c]-pyrazoles may be performed by the method of Clinton et al. (J. Am. Chem. Soc. 81, 1513 (1959)) by reacting 3-keto-2-hydroxymethylene retro-steroids with hydrazine. Thus, 2-hydroxy-methylene-retro-pregn-4-ene-20-ol3-one by reaction with hydrazine yields 20 hydroxy-retro-pregn' 4-eno- [3,2-c]-pyrazole. Further, reaction of 2-hydroxy-methylene- 6-dehydro-retro-testosterone with hydrazine gives 17,3-hydroxy-retro-androsta-4,6dieno-[3,2-c]-pyrazole.

The preparation of oxido IOa-methyl 9fi-steroids can be performed by reacting a double bond between the carbon atoms under consideration with an oxidizing agent such as hydrogen peroxide in the presence of an alkali or with an organic peracid such as monoperphthalic acid. Thus 6-dehydro-retro-progesterone when reacted with monopherphthalic acid yields 6,7-oxido-retro-progesterone.

The introduction of methylene groups into wot-methyl 9fl-steroids may be eflected by the addition of diazomethane to the double bond present in such a steroid and cleavage of the thus obtained pyrazolines according to the procedure of Wiechert and Kaspar (Chem. B612, 93, 1810 (1960)). Thus 16-dehydro-retro-progesterone may be converted into 16-methylene-retro-progesterone.

The introduction of thiol groups (SH) into methyl 9li-steroids 'may be effected as follows:

The reaction of a steroidtosylate with thiourea and splitting of the thus formed isothiouromium compound with alkali hydroxide affords the desired thiol 10a-methyl 9,8-steroid. Thus 3-thiolo-androst 4-en-175-o1 17-acetate can be prepared from 3-tosyloxy-androst-4-en-17,8-01 17- acetate.

The introduction of the thio analogues of alkoxy and aralkoxy groups into IOa-methyl 9fi-steroid-s can be effected by reacting an oxo-lOa-methyl, 9fl-steroid with an alkyl thiol or an aralkyl thiol respectively in the presence of a catalyst such as p-toluene sulphonic acid. Thus retrotestosterone when reacted with ethyl Inercaptane yields 3- enol ethyl thio ether and when reacted with benzylmercaptane yields 3-enol benzylthioether of retrotesterone.

The preparation of 2-methyl-(3,2-d)-thiazoles may be carried out according to the process described by Doorenbos et al. (J. Pharm. Sc. 50, 271 (1961)), by reacting 2-bromo-3-keto retrosteroids with thiacetamide. Thus 2- bromo 17a-methyl-retrotestosterone may be converted into 2-methyl (3,2-d) thiazolo 17a-methy1-retro-androsta-2,4-dien-17-ol.

The synthesis of 2'-amino-(3,2-d)-pyrimidino retrosteroids may conveniently be performed by the reaction of 2-hydroxy methylene-3-keto-retro-steroids with guanidine according to the process described in Bull. Off. de la Trop. 1nd. 1, 344 (1961). Thus 2-amino-(3,2-d)-pyrimidino-retro-andro-stra 4,6-dien-17fi-ol 17-acetate can be prepared from 2 hydroxymethylene 6 dehydro-retrotestosterone 17-acetate.

The production of 6-nitro retro-steroids may be efiected by nitration of 3,5-dienylacylates of retrosteroids as described by Bowers et al. (J. Am. Chem. Soc., 81, 3707 (1959)). Thus, 3,17u-diacetoxy-retro-pregna-3,5-dien-20- one can be converted into 6-nitro-l7a-acetoxy-retro-progesterone.

The introduction of an oxygen atom in the 18-methyl group in retrosteroids can for instance be carried out by the irradiation of a ll-nitrite of 1l-hydroxy-retro-steroids according to the process described by Barton et al. (J. Am. Chem. Soc. 82, 2641 (1960)). Thus retro-corticosterone 21-acetate can be esterified into the corresponding 11- nitrite. Irradiation of this compound in toluene yields the retro-aldosterone 21-acetate oxime, which can be transformed by the action of sodium nitrite in acetic acid into retro-aldosterone ZI-acetate.

Retro-17-spirolactones may be prepared by reaction of a l7a-acety1enic substituted retro steroid with an alkyl Grignard halide, decomposing the complex thus formed with carbon dioxide and after hydrogenation lactonizing the thus formed hydroxy acid, as described by Cella et al. (J. Org. Chem. 24, 743 (1959)). Thus 17a-ethinyl-3,17- dihydroxy-retro-androst S-ene is converted into 3,17-dihydroxy-retro-androst 5-en-17a-ylpropynoic acid, after which catalytic hydrogenation yield-s 3-(3,17-dihydroxyretro-androst 5-en-17a-yl) propenoic acid lactone. Repeated hydrogenation gives the corresponding 17-propa noic lactone, which by means of an Oppenauer-oxidation can be converted into the 3keto-A -retro-spirolactone.

Tn'halomethyl-retrosteroids can be prepared by the reaction of enol ethers of unsaturated ketones with tetrahalomethanes as described by Lusberg et al. (Tetrahedron 9, 149 (1960)). Thus the reaction of the A -enolethyl ether of retro-progesterone with tetrabromomethane yields 6-tribromomethyl-retroprogesterone. In the same manner the trifiuoro and trichloro compounds may be prepared. The latter compound can by splitting 01f HBr and/or reduction be converted in 6-methyl-retro-progesterone.

The methods of preparing the novel retrosteroids of our invention will now be explained in greater detail in the examples which follow.

Example 1 (a) By very vigorous stirring, 125 g. of A4332 lumistatri'en 3 one were dissolved at 10 C. in 2.2 litres of dry propanol 2, which had previously been saturated with dry hydrochloric acid gas. The hydrochloric acid gas was slowly passed through the liquid for an additional half hour. The liquid was then decanted as rapidly as possible, While stirring, into a mixture of solid sodium bicarbonate and a saturated bicarbonate solution, obtained by stirring 4 kg. of sodium bicarbonate with 8 litres of water. After a short period of time the yellowish propanol 2 layer was separated out and the salt layer extracted twice with one litre of petroleum ether. The combined layers were then washed three times with a sodium bicarbonate solution and water, then dried on sodium sulphate and evaporated to dryness after filtering. The ultraviolet absorption spectrum exhibited a maximum at 287 mg, of which the El' g is 562 (content of pure substance about 85% The residue obtained was dissolved in 250 ml. of boiling petroleum ether (40 to 60 C.) and crystallized at 5" C. for a few hours and finally overnight at C. Filtering yielded 80.5 g. of lumista 4,6,22 trien 3- one with a melting point of 99 to 100.5 C. (yield 64% A portion of the last substance was recrystallized a few times with petroleum ether for analysis, the melting point rising to 101102 C. The further analytical values were:

=632 (CHCl e ().==287 m =26200. Found: C, 85.67%, 85.68%; H, 10.65%, 10.77%. Calculated for C H O: C, 85.22%; H, 10.73%.

In the infrared spectrum there were found apart from the 964 C111. 1 band for the side chain trans-ethylene bond three characteristic bands at 1586, 1622 and 1661 cmr (b) While stirring vigorously, a solution of 3.0 g. of lumista 4,6,22 trien 3 one in 300 ml. of dry diethylether was added to 450 ml. of liquid ammonia. During the addition of the first portion of the solution crystallization occurred but the solid dissolved after a larger portion had been added. Then, while stirring vigorously, a solution of 420 mg. of lithium in 100 ml. of ammonia was carefully added in drops, until no spontaneous decoloring occurred any more. 90 ml. of dry ethanol were then added dropwise, stirring was continued for 30 minutes, the mixture was diluted with water and the reduction product was dissolved in diethyl ether. The ethereal extracts were then extensively washed with water, dried on Na SO filtered and evaporated to dryness yielding a light-yellow resin.

(El fi (A max. 242 m )=196) The resin was dissolved in 100 ml. of boiling ethanol and 'after the addition of 6 ml. of 2 N NaOH the solution was boiled for five minutes. The solution was then rapidly cooled. By diluting with water, absorbing in diethyl ether, washing of the ethereal layers with water, drying, filtering and evaporating to dryness, a light-brown residue was finally obtained with E1 3, (A max. 242 m;;)=420 This substance was chromatographed in 25 ml. of pure benzene on 30 g. of A1 0 (HI) and eluated with the same solvent (total m1.), a dark brown ring remaining at the upper end of the column. The dry eluate was recrystallized with 45 ml. of methanol at 5 C., after which the filtered product was washed with 20 ml. of methanol of 25 C. The yields were long light-brown needles 1.5 to 2 cm. in length), weight 2.43 g. and melting point 122 to 124 C.

500 g. of this substance were recrystallized twice with 3 ml. of acetone at .5 C., after which finally 313 mg. of colorless crystals of lumista 4,22 dien 3 one were obtained.

The analytic values found for this pure substance were:

6 ('y 2 42 m 1'6.800, melting point l2 2-l24 C. [u] 1-25 (CHClg). Found: C, 84.98%, 84.89%;1-1, 10.96%, 11.03%. Calculated for C H O=C, 84.79%; H, 11.17%.

In the infrared spectrum an intense band was found at 1665 CH1."'1, a slightly weaker band at 1620 crnf a weak band at 962 cmf and a slightly more intense band at 978 CH1. 1. V

20 g. of lumista 4,22 dien 3 one was dissolved in a mixture of 750 ml. of freshly distilled methylene chloride and 5.75 ml. of dry pyridine. The mixture, while being stirred magnetically at C. (carbon dioxide ice and acetone) for 4 /2 hours was ozonised (0.205 mol ozone per min), speed of passing oxygen (VQ2):9 to 10 l./hour. The ozonide formed was then decomposed at 0 C. for one hour by stirring it with a suspension of 20 g. of zinc powder, after the addition of ml. of glacial acetic acid. The reaction mixture was then warmed for 5 minutes at 35 C., and then the resultant solid substance was separated out by filtering. After the addition of ice the filtrate was washed successively with 75 ml. and 50 ml. of ice cold 10% Na CO solution, three times with 50 ml. of 10% NaOH solution at 0 C. and four times with 300 ml. of ice water.

The methylene chloride layer was then dried on Na SO filtered and the filtrate was distilled to dryness, the last part of which was carried out in vacuo. The colorless, practically completely crystalline residue was recrystallized with 50 ml. of diethylether at 25 C., the first crystallate being 10.1 g. of 3 keto retro bisnorchol 4 en 22 al with a melting point of 119 to 121 C. This material was further purified by a few recrystallizations with petroleum ether (boiling region 40 to 60 C.) to which a few drops of ethyl alcohol had been added, and with diethylether.

The analytic values of this pure substance were:

M.P. 122-130 C. e (A max. 242.5 mp.)=16,700, [a] =144 C. (CHCl Found: C, 79.87%, 80.06%; H, 9.73%, 9.8%. Calculated for C H O C, 80.42%; H, 9.82%.

The infrared spectrum showed characteristic bands at 1712, 1642 and 1610 cmf (c) A solution of 450 mg. of 3-keto-retro-bisnorchol- 4-en-22-al obtained as described in Example 1(b) in 15 ml. of chloroform and 25 ml. of acetic acid, in which 200 mg. of chromic acid and 0.2 ml. of water had beendissolved was oxidized at about 30 C. for 16 hours.

After the excess quantity of chromic acid had been decomposed by stirring for 30 minutes with 1.5 ml. of methanol, the mixture was diluted with water and the substance was dissolved in benzene. The benzene extract was washed with water to neutral reaction, dried on Na SO and filtered. After evaporation to dryness a crystalline residue was obtained, which by crystallization with diethylether, yielded 340 mg. of 3-keto-retro-bisnorchol-4-enic acid, melting point 194 to 198 C. A few 29 crystallizations raised the melting point of this substance to 202 to 204 C.

The further analytic values found for this pure substance were:

5 (A max.=242 m )=16,800. Calculated for: 1-1 0 C, 76.70%; H, 9.36%. Found: C, 76.93%, 76.92%; H, 9.45%, 9.48%.

(d) A solution of 450 mg. of an ozonide in 25 ml. of methylenechloride obtained in the manner described in Example 1( b), by ozonizing lumista-4,22-dien-3-one, was oxidized with a solution of 200 mg. of chromic acid in 25 ml. of acetic acid overnight at 30 C. The excess quantity of chromic acid was then decomposed by stirring with 2 ml. of methanol for 30 minutes.

After dilution with water, the mixture was dissolved in diethyl ether and the ether methylene chloride extract was washed three times with 50 ml. of 2% NaOH. These layers were combined, extracted again with diethylether to remove residues of neutral constituents. The organic acid was freed by acidfying with concentrated hydrochloric acid and dissolving in diethylether. After neutral washing with water, the mixture was dried on Na SO filtered and finally evaporated to dryness; the yield was 240 mg. of crystalline residue. A crystallization with methanol at C. yielded 150 mg. of 3-keto-retrobisnorchol-4-enic acid with a melting point of 200 to 203 C. When this acid was mixed with 3-keto-retrobisnorchol-4-enic acid as obtained by the method described in Example 1(c) no drop in the melting point occurred.

(e) 0.11 ml. of dry, freshly distilled piperidine and 1 to 5 mg. of p-toluene sulfonic acid were added to a solution of 300 mg. of 3keto-retro-bisnorchol-4-en-22-al as obtained by ozonization of lumista-4,22-dien-3-one. This solution was then refluxed in 5 ml. of dry benzene for 3 hours under N The refluxing benzene was dried by being passed through powdered BaO in an extraction column.

After cooling, the reaction mixture was poured out into water, dissolved in diethylether and then washed adequately four times with water. The ether-benzene layer, dried on Na SO and filtered, was dried to complete dryness in vacuo. The resinous residue was stirred with 3 ml. of methanol at 15 C., cooled to 25 C. and kept at that temperature for 2 hours and crystallized. Filtering of this solution yielded 185 mg. of needles with a melting point of 88 to 93 C. of 22-(N-piperidyl)retro-bisnorchola-4,20 (22) dien-3 one.

Two recrystallizations with methanol raised the melting point of this substance to 9496 C.

The analytical values of this pure substance were:

e (A max. 241.5 m =21.800, [a] =-l39 (CHCl Found: C, 81.72%, 81.78%; H, 10.64%, 10.67%; N, 3.60%, 3.66%. Calculated for C21H41NO: C, 81.97%; H, 10.45%; N, 3.54%.

The infrared spectrum exhibited an intensive band at 1660 cm. which overlapped distinctly a band with lower extinction at 160 cm. Apart from a band at 1610 cm. a weaker band was found at 874 cm.-

After a few small charges of the above-mentioned piperidino compound were produced in a similar manner, in which the final substance had a melting point of 94 to 96 C., production of several more larger charges of this compound in a different manner was carried out. The resultant compound which had a different melting point (114 to 115 C.) was then obtained in large yields. Probably this effect is due to cis-trans isomerism.

This alternate method of preparing this compound was carried out as follows:

A solution of g. of 3keto-retro-bisnorchol-4-en-2-a1 was refluxed in 180 ml. of dry benzene with 3.8 mls. of piperidine and 30 ml. of p-toluenesulphonic acid for 3 hours under nitrogen. The refluxing benzene was dried by passing through powdered barium oxide.

The reaction mixture was evaporated to complete dryness in vacuo, a crystalline residue of 12.3 g. being obtained. Recrystallization with 10 ml. of methanol yielded 9.3 g. of 22-(N-piperidyl) retro-bisnorchola-4,20(22)- dien-3-one, melting point 98 to 107l11 C. A portion of this substance, which was sufficiently pure for further processing, was recrystallized a few times with acetone for analysis until a constant melting point of 114115 C. was attained.

The analytical values of this substance were:

6 (A max. 241.5 m ):22.000.

C, 81.87%, 81.98%; H, 10.49%, 10.47%; N, 3.42%, 3.63%.

The infrared spectrum of this substance differed only on details from that of the compound having a melting point of 94 to 96 C. The characteristic bands found for said substance were also found in this case.

(f) 0.5 g. of freshly melted sodium acetate was added to a solution of 1 g. of 3ketoretrobisnorchola-4-en-22- al, obtained as described in Example 1(b), in 50 ml. of freshly distilled acetic acid anhydride. This mixture was then refluxed in a nitrogen atmosphere.

The solvent was then distilled off as far as possible under reduced pressure (about 10 minutes) and the residue obtained was dissolved in 25 ml. of chloroform. Undissolved sodium acetate was filtered oi, the filter was washed with a small quantity of chloroform and the filtrate was diluted with the same solvent to ml., a solution of 22-acetoxy-retro-bisnorchola-4,20(22)-dien-3-one being obtained.

(g) A solution of 300 mg. of 22-(N-piperidyl)-retrobisnorchola-4,20(22)dien-3-one in 4.5 ml. of dry thiophene-free benzene, was added dropwise at a temperature of 5" C. to +5 C., in 45 minutes, while stirring, to a solution of 453 mg. of sodium bichromate dihydrate in 4.5 m1. of acetic acid and 3 ml. of benzene. After additional stirring, for 2 hours at 0 C., 0.75 ml. of methanol was added to the dark-colored solution and stirring was continued for 30 minutes also at 0 C.

This reaction mixture was then processed by pouring it out into 25 ml. of water and by extraction twice with benzene. The combined benzene extracts were then washed successively with water, 3 ml. of cold 10% NaOH solution, twice with water, 3 ml. of cold 10% hydrochloric acid solution and four times with water. The solution was .then dried on Na SO filtered and evaporated to dryness producing a completely crystalline residue.

This residue was dissolved in 1 ml. of methylene chloride and 4 ml. of petroleum ether was added to boiilng temperature. The crystallization which was completed at 25 C. yielded 150 mg. of light-yellow, hard crystal blocks of retro-progesterone with a melting point of 161 to 163 C.

A repeated recrystallization of this substance yielded mg. with a melting point of 163-164 C.

The analytical values of this pure substance were:

6 ()t max. 241.5 mn)=16,800.

Found: C, 79.90%, 79.89%; H, 9.75%, 9.75%. Calculated for C H O C, 80.20% H, 9.62%.

The infrared spectrum exhibited strong bands at 1690 cm. and 1662 cmf and a weaker band at 1615 cm."

(h) 0.5 g. of freshly melted sodium acetate was added to a solution of 1 g. of 3ketoretro-bisnorchol-4-en-22-al, obtained as described in Example 1(b), in 50 ml. of freshly distilled acetic acid anhydride and the mixture was refluxed for 16 hours in a nitrogen atmosphere.

Then the solvent was distilled off as far as possible under reduced pressure (about 10 mm. Hg) and the residue obtained was dissolved in 25 ml. of chloroform. The undissolved sodium-acetate was filtered off, the filter was washed again with a small quantity of chloroform and 31 the filtrate Was increased with the same'solvent to 150 mls. A solution of 22-acetoxy-retro-bisnorchola-4,20(22)- dien-3-one was obtained.

While cooling with ice water this solution was ozonized for 14 minutes, 10.5 mg. of ozone being absorbed per minute. Then, after the addition of 15 ml. of acetic acid and 2 g. of zinc substance for minutes, the mixture was shaken and after filtering the solution was washed with 10% NaOH solution and Water to neutral reaction. The solution was dried on Na SO filtered and evaporated to dryness, and then refluxed to hydrolyse any 3- enolacetate present for 45 minutes in 45 ml. of methanol and 25 m1. of 2 N H 50 After concentration in vacuo down to halt the volume the solution was dissolved in diethyletber. The ethereal extract was washed with 10% NaOH solution and water to neutral reaction dried on Na SO evaporated to dryness and finally crystallized with 3 ml. of diethyl ether. The crystallate obtained was recrystallized with a mixture of methylene chloride and n-hexane, the yield being 113 mg. of substance with a melting point of 160-163 C. The substance did not exhibit a reduction in melting point with the retro-progesterone obtained as described in Example 1( g).

[u] =61.5 (CHCl (mean value of 62.1 an 60.9

The iollowing compounds listed with their starting materials are prepared according to the methods of EX- ample 1:

7-dehydro-retro-progesterone from lumista-4,7,22-

trien-3-one;

6-dehydro-retro-progesterone from lumista-4,6,22-

trien-B-one;

1-dehydro-retro-progesterone from lumista-1,4,22-

trien-3-one;

retro-pregna-1,4,6-triene-3,20-dione from lumlsta- 1,4,6,22-tetraen-3-one;

retro-pregnane-3,20-dione from lumist-22-en-3-one;

Z-methyI-retro-progesterone from Z-methyl-lumista- 4,6,22-trien-3-one;

6-rnethyl-retro-progesterone from 6-methyl-lumista- 4,22-dien-3-one;

6-fiuoro-retroprogesterone from 6-fluoro-lumista- 4,22-dien-3-one;

6-chloro-retro-progesterone from 6-chloro-lumista- 4,22-dien-3-one;

6-hydroxy-retro-progesterone from 6-hydroxy-lumista- 4,22-dien-3-one;

4-chloro-retro-progesterone from 4chloro-lumista- 4,22-dien-3-one;

1-methyl-retro-progesterone from l-methyl-lumista- 4,22-dien-3-one;

2-hydroxy-retro-progeste-rone from 2-hydroxy-l-umista- 4,22-dien-3-one;

retro-pregn-S-ene-3,20-dione from lumista-5,22-

dien-3-one;

9-fiuoro-11-hydroxy-retro-progesterone from 9-fluoro- 1 1-hydroxy-1umista-4,22-dien-3 -one;

16-hydroxy-retroprogesterone from 16-hydroxy-lumista- 4,22-dien-3-one;

16-methyl-retro-progesterone from l6-methyl-lumista- 4,22-dien-3-one;

3-hydroxy-retro-pregn-5-en-20-one from 3-hydroxylumista-5,22-diene; and

3-hydroxy-retro-pregnan-20-one from 3-hydroxylumist-ZZ-ene.

Found: C, 74.03%, 74.27%; H, 8.55%, 8.77%.

The infrared spectrum exhibited bands at 1226, 1609, 1663, 1724 and 1751 cm.-

The following compounds, listed with their starting materials are prepared according to the methods used in Example 2:

21-acetoxy-6-dehydro-retro-progesterone from 6-dehydro-retro-progesterone;

From all the above named compounds there can be prepared the unesterified corresponding 21-hydroxy derivatives by mild hydrolysis methods described in literature, for instance by reacting the esters with dilute alkali as potassium hydroxide or potassium bicarbonate.

Example 2 (a) A solution of 4.08 g. of bromine in 50 ml. of methylene dichloride was added in drops while stirring at 55 C., in a nitrogen atmosphere to 9.6 g. of 22- (N-piperidyl) -retro-bisnorchola-4,20 (22) -dien-3-one obtained as described in Example 1(e) and dissolved in 475 ml. of methylene dichloride. After the addition of 47 ml. 7

of the bromine solution the mixture assumed a lightbrown color, at which point the addition was stopped. Thus 22-(N-piperidyl)-20,22-dibromo retro-bisnorchol-4- en-3-one was obtained. After the reaction mixture had been warmed up to 0 C., 60 ml. of water were added and stirring was carried out vigorously at 20 C. for 2 hours. The methylene dichloride layer then was separated and washed twice with mls. of water and dried on Na SO The residue contained 20-bromo-retro-bisnorchol-4-en-3-on-22-al. To the. filtered methylene dichloride solution 70 mls. of dry pyridine were added and the methylene dichloride was distilled off in vacuo; Then dehydrobromination was carried out by heating the solution under N for 60 minutes, at 70 C. and then for 30 minutes at 100 C. Distilling off the pyridine in vacuo then yielded a residue, which was dissolved in methylene dichloride and .then washed successively with 2 N HCl three times with water and three times with 5% Na CO solution in water. After this, the resultant mixture-was dried on Na SO filtered and evaporated to dryness. The yield was a light-brown crystalline residue with a melting point of (s)l53-155 and EH3, (A max.=248 m =865 Recrystallization from 30 mls. of acetone at 5 C. yielded 6 g. of 3-keto-retro-bisnorchola-4,17(20)-dien-22- al with a melting point of 154(s)155158 C. A small quantity of this substance was crystallized, in order to obtain a pure preparation for analysis, three times with acetone and once with ethanol. The analytical values of this purified product were as follows:

Melting point 151(s)155159 C. [a] =l38 (CHCl 3 E12, ()t max. 248 m :914 7 Calculated for C H O i C, 80.98%; H, 9.20%. Found: C, 80.95%, 80.82%; H, 9.10%, 9.14%.

The infrared spectrum exhibited a strong 'band at 1665 cmr a shoulder at 1710 cm? and a weak band at 1620 cm.- It is not possible, in view of the lack of sharpness of the melting point, that a mixture of cistrans isomers is obtained.

(b) 48 ml. of a bromine solution in CC].; (0.515 mol per ml.) was added while stirring vigorously in a nitrogen atmosphere to a solution of 7.7 g. of 3-keto-retrobisnorchol-4-en-22-al (obtained as described in Example 1(b) in 100 ml. of dry carbon tetrachloride, in which 3 g. of powdered calcium carbonate had been suspended. By this reaction 20-bromo-retro-bisnorchol-4en 3 on- 22-al was formed. During the dropwise addition of the bromine solution, which took 75 minutes, a brown deposit was formed in the reaction mixture. The resultant mixture was then filtered and washed with methylene dichloride, the organic portion of the deposit being thus dissolved. The filtrate was then washed in succession twice with NaHCO solution and twice with water, dried on Na SO and then 25 ml. of dry pyridine were added. The solution was then filtered to remove the inorganic salt and evaporated to dryness in vacuo until the final volume was about 20-30 ml. Pyridine was then added again and dehydrobromification was carried out by heating under nitrogen at 70 C. for 60 minutes and for another 30 minutes at 100 C.

The pyridine was distilled off, as far as possible, in vacuo from the dark-colored solution. Crystallizaton of pyridine HBr occurred. The organic constituent of this solution was dissolved in methylene dichloride and the solution obtained was successively washed twice with 2 N H 80 once with water, once with 5% NaHCO solut'on and once with water. This solution was then dried on Na SO and filtered by means of a small quantity of carbon, and finally evaporated to dryness, 7.15 g. of crystalline residue being thus obtained.

Eff (A max. 246.5 m =630 By recrystallization of this residue pure 3-keto retro-bisnorchola-4,17(20)-dien-22-al was obtained.

(c) 5 g. of powdered 3 keto -ret-ro -bisnorchola 4, 17 (20)-dien-22-al was suspended with stirring in a solution of 8 g. of NaCN in 50 ml. of absolute methanol cooled to 20 C. To this suspension there were added by dropwise addition within about 45 minutes 7.1 mls. of glacial acetic acid while the suspension was held at 20 C. Within about 2 hours, the reaction temperature was raised from 20 C. to 5 C. The white paste obta ned was kept at 5 C. for 40 hours, after which it was processed by pouring it out into 150 ml. of methylene dichloride at C. and washing in succession with 75 ml. and then four times with 25 ml. of ice water and drying on Na SO at C. for overnight.

A small portion of the filtered solution was evaporated to dryness. The nitrogen content of the practically colorless residue found was 4.20% (theoretical value 3.96%) and El'flj (A max. 244 m +535 (methanol), Eii

(X max. 233 m u)=5l6 (diethylether) The compound thus obtained was the ZZ-HCN-addition product of 3-keto-retro-bisnorchola-4,17(20)-dien-22-al. The remainder of the filtrate was ozonized at 80 C., while stirring, after 1.5 ml. of dry pyridine had been added. The duration of the ozonization was 75 minutes (per 10 min. 2.16 mol 0 the speed of the gas being about 10 /2 hours.

The reaction mixture was then decomposed by stirring it for 2 hours with 5 g. of zinc powder and ml. of glacial acetic acid, the temperature rising slowly to C. The filtered solution was then washed with water (150 ml. and twice with 100 ml), twice with 50 ml. of 10% NaOH solution twice with water, 50 ml. of 10% HCl solution and three times with water, dried on Na SO and after filtering, evaporated to dryness. A few recrystallizations with ethanol yielded 1.48 g. of retroandrost-4-en-3,17-dione, melting point 153155 C. A portion of this crystallate was recrystallized for analytical purposes with 90% and 96% ethanol and yielded a pure product having the following analytical values:

34 Melting point 154156 C. Calculated for C H O C, 79.68%; H, 9.15%. Found: C, 78.93%, 79.20%; H, 9.24%, 9.22%.

Elfi (X max. 2t0.5 m =16,200

The infrared spectrum exhibited strong bands at 1735 and 1665 cmf Example 3 50 ml. of ammonia was liquified at C. in a threenecked round-bottom flask of 250 ml. capacity. The ammonia gas had previously been dried by passing it through three drying towers containing solid KOH, soda lime and KOH respectively. In the liquid ammonia there was then dissolved 1.61 g. of potassium, after which in the resultant deep-blue solution acetylene gas was introduced until a complete decoloring had taken place. This gas had been dried and purified by means of solid KOH, soda lime, KOH, concentrated H 50 and solid KOH in succession.

To the acetylide thereby produced there was then rapidly added, while stirring and cooling, at 80 C., 1.06 ml. of dry acetone, after which a solution of 3.03 g. of retroandrost-4-en-3,17-dione in a mixture of 25 ml. of dry thiophene-free benzene and 25 ml. of dry peroxide-free diethylether was immediately added.

The reaction mixture was then allowed to remain in a slow stream of dry nitrogen without external cooling for 16 hours. The reaction mixture was decomposed with ml. of water. The clear benzene layer thus separated out and was processed by washing it with water, drying on Na SO filtering and evaporating to dryness. The 3.25 g. of residue tta... max. 242 111,4):288)

was chromatographed in benzene on 50 g. of A1 0 (strength according to Brockmann II).

Eluation with benzene (800 ml.) and diethylether (200 ml.) yielded crystalline fractions, which were combined and recrystallized with n-hexane, from which 1.95 g. of needles of 17a-ethynyl-retro-testosterone with a melting point of 194-196 C. was obtained.

A small portion of this substance was recrystallized for analysis a few times from n-hexane to produce a pure product having a constant melting point of 195-196 C. and in which the other analytical values were:

Found: C, 80.88%, 80.83%. H, 8.98%, 9.11%. Calculatfid for 0211 12302: C, H, 9.03%-

The infrared spectrum of the substance exhibited, inter alia, more or less strong bands at 877, 1063, 1128, 1222, 1604 and 1648 cm.

According to the method described in this example the following compounds are prepared:

17-prop-1-ynyl-retro-testosterone; 17-but-1-ynyl-retro-testosterone; 21,21-dimethyl-retro-ethisterone from retro-androst-4- ene-3,17-dione; 6-dehydro-17-prop-1-ynyl-retro-testosterone from retroandrost-4,6-diene-3,17-dione; and 17-ethynyl-16-methyl-retro-testosterone from 16-methylretro-androst-4-ene-3,17-dione.

Example 4 (a) A solution of 7.5 g. of retro-progesterone in 500 ml. of freshly distilled tertiary butyl alcohol was refluxed with 12.75 g. of finely powdered chloranil, while stirring, for 5 hours in a nitrogen atmosphere. After cooling, 2 litres of water were added and extraction was performed three times with 200 ml. of methylene dichloride. The combined extracts were then diluted with 1 litre of petroleum ether (4060 C.) washed successively with 100 ml. of diluted Na SO (100 ml.) four times with 75 ml. of 1 N NaOH and water to neutral reaction.

By drying this solution on Na SO and evaporating to dryness (last part in vacuo) 3.7 g. of crystalline residue was obtained.

This residue was then dissolved in benzene.

Filtration in benzene filtered through via 35 g. of alumina (according to Brockmann, strength II) and then the alumina was eluated with benzene. Evaporation of the benzene yielded 3.11 g. of crystalline residue. By crystallization with 15 ml. of acetone at room temperature (at lower temperatures a by-produet crystallized out) 900 mg. of crystallate with a melting point of 165170 C. were obtained. Transfer of the acetone mother liquor into a mixture of ethanol and hexane yielded 1.7 g. of a solid substance with a melting point of 130 to 145 C. This solid was then recrystallized with acetone at room temperature, yielding 600 mg. of a solid with a melting point of 166 to 171 C. The two fairly pure fractions (600 mg. and 900 mg.) yielded, after crystallization with a mixture of acetone and hexane, finally 1.0 g. of 6-dehydro-retro-progesterone, melting point 169 to 170 C. From the mother liquors an additional fraction of 0.44 g. with a melting point of 168 to 169 C. was obtained.

A small portion of the 6-dehydro-retro-progesterone was recrystallized with acetone for analysis and had the following analytical values:

Melting point 169170 C.

Ei'fi' (A max.=286.5 m =842 and 848, e (A 286.5 m =26,400

Calculated for C H O (311,43): C, 80.73%; H, 9.03%. Found: C, 81.11%, 81.25%; H, 9.20%, 9.07%.

The infrared spectrum exhibited inter alia bands at 1695 cmf (strong, non-conjugated keto-group), 1656 cm? (strong, conjugated keto-group), 1617 cm. (strong, double bond in conjugation), 1574 cm.- (moderately strong, double bond) and 888 em- (strong).

According to the method described in this Example 4(a) the following compounds listed with their starting materials are prepared: l,6-bisdehydro-retro-progesterone from l-dehydro-retro-progesterone; 2-methyl-6-dehydro retro-progesterone from 2-methyl-retro-progesterone; 1,6- bisdehydro 17oz hydroxy-retro-progesterone 17-acetate from l-dehydro-17a-hydroxy-retro-progesterone 17-acetate; 6-dehydro -9 -fiuoro-retro -hydrocortisone from 9- fluoro-retro hydrocortisone; 6-dehydro 16 hydroxy-9- fiuoro-retro-prednisolone from 16-hydroxy-9-fluoro-retroprednisolone; 6-dehydro-16-methyl-9-fiuoro-retro-prednisolone from 16-methyl-9-fluoro-retro-prednisolone and 6- dehydro-retro-desoxycorticosterone 2l-acetate from retrodesoxycorticosterone 21-acetate.

(b) 3.95 g. of the isolumisterone obtained as described in Example 1(a) were dissolved in 150 ml. of dry methylene dichloride. To this solution there was then added 0.81 ml. of dry pyridine. The solution thus obtained was cooled to 80 C. and then, within 26 minutes, 15 mmols of ozone (i.e. 140% of the theoretical volume) was passed through. The reaction mixture was then vigorously stirred, after which 15 g. of para-formaldehyde was added. Under constant stirring the temperature rose Within 4 hours to about room temperature. After standing overnight the solid substance was filtered off, washed with petroleum ether and diethyl ether. The ether solution was then extracted with water, cold 1 N NaOH and water. After drying on Na SO this solution was evaporated and 3.08 g. of residue were obtained.

13... (A max. 286 m,. =7

This residue was crystallized from acetone and then re crystallized twice from acetone. The resultant pure 3- keto-retro-bisnorchola-4,6-dien-22-al had a melting point of 153155 C. The other analytical values of this substance were as follows:

The ultraviolet absorption spectrum had a maximum at 286 my.

Calculated for C I-1 0 (326.48): C, 80.94%; H, 9.26%; O, 9.80%. Found: C, 81.07%, 80.87%; H, 9.16%, 9.05%; O, 9.94%, 10.00%.

The following bands in the infrared spectrum were found: 1410 cm.- (weak), 1654 cm? (strong), 1717 cm." (strong), 1584 emf- (strong), 1621 cm? (fairly strong).

(c) 3.5 g. of 3-keto-retro-bisn0rchola-4,6-dien-22-al obtained as described in Example 4(b) (crude crystalline form, melting point 146151 C.) were dissolved in 50 ml. of absolute benzene. To this solution there was then added 1.27 ml. of piperidine and 20 mg. of p-toluenesulphonic acid. This reaction mixture was refluxed for two and a half hours and the refluxing benzene dried with BaO. Then the solvent was distilled off in vacuo and 4.4 g. of residue was left This residue was crystallized from 30 ml. of methanol at 25 C. Yield: 2.1 g. of 22- (N-piperidyl) -retro-bisnorchola-4,6,20 (22 -trien-3 one with a melting point of 127-135 C. After two recrystallizations with acetone this substance was pure. The analytical values of this material were as follows:

Melting point (in vacuo) 136 C. Ultraviolet absorption spectrum had a maximum at 287 my Ef g =66l and 657, e=26,000 and 25,800

Calculated for C H NO (393.62): C, 82.39%; H, 9.99%; O, 4.06%; N, 3.56%. Found: C, 82.40%; H, 9.86%; O, 4.35%; N, 4.13%.

There were found bands in the infrared 870 cm? (strong), 1656 cm." (strong), (strong) and 1410 GEL-1 (weak).

(d) 16.7 g. of 22-(N-piperidyl)-retro-bisnorchola- 4,6,20(22)-trien-3-one obtained as described in Example 4(c) and dissolved in 250 ml. of dry thiophene-free benzene, were added in drops, in 45 minutes, to an adequately stirred solution of 25.2 g. of sodium bichromate in 250 ml. of acetic acid +170 ml. of benzene cooled to 0 C. After two hours of stirring at 0 C., 42.0 ml. of methanol were added and stirring was continued for half an hour at 0 C. The reaction mixture was then poured out in water and extracted with ether. The extract was washed with water, diluted sodium hydroxide solution and water. After drying on Na SO the solvent was distilled off. Yield: 12.24 g. (92%) of residue. This residue was crystallized with acetone-hexane (6.6 g.) and then by two crystallizations with acetone the substance obtained was pure. The melting point of the 6-dehydroretro-progesterone thus obtained was 168-169 C.

(e) 3.95 g. of lumisterone were dissolved in ml. of dry methylene dichloride and .to this solution there was added 0.81 ml. of pyridine. This solution was then cooled to 70 C. and within 26 minutes, 14 mmols of ozone was passed through. Then 15 g. of paraformaldehyde were added and, while stirring, the temperature was slowly raised to +5 C. The paraformaldehyde was filtered off, and washed with methylene dichloride. The filtrate was washed with water, 1 N NaOH solution and Water. After drying on Na SO the organic solvent was distilled off, after which 3.11 g. of crystalline residue was left. This residue was recrystallized with a mixture of methylene dichloride and acetone. After three recrystallizations pure 3-ket0-retro-bisnorchola-4,7-dien-22-al was obtained with a melting point of 196200 C. and the following analytical values:

The ultraviolet absorption spectrum had a maximum at 241 m r.

E}"; =433 and 436, e=14,150 and 14,200

Calculated for C H O (326.48): C, 80.94%; H, 9.26%; O, 9.80%. Found: C, 80.15%, 80.28%; H, 9.1%, 9.09%; O, 10.10%, 10.04%.

The infrared absorption spectrum had bands, inter alia, at 1410 cm. (weak), 1660 cm.* (strong), 1610 cm.- (strong) and 1714 cn1. (strong).

spectrum at 1622 cm.-

37 When the aldehyde thus obtained was converted in the manner described in Example 1(e) or 4(0) into 22-(N- piperidyl)-retro-bisnorchola 4,7,20(22)-trien-3-one, and this compound was oxidized with sodium bichromate in benzene and acetic acid in the manner described in Ex ample 1(g) or 4(d), 7-dehydro-retro-progesterone was obtained. By isomerisation of the 3-keto-4,7-dehydro-system of this latter compound into the 3-keto-4,6-dehydrosystem with dry HCl-gas in anhydrous isopropanol, in the manner described in Example 1(a), the 6-dehydr0- retro-progesterone is obtained.

Example 5 (a) A solution of 1.2 g. of monoperphthalic acid (6.6 mols) in 25.5 ml. of ethylacetate at C. was added to an ice water cooled solution of 0.978 g. (3 mols) of 3- keto-retro-bisnorchol-4,20(22)-dien-22-al obtained as described in Example 2(a) or 2(b) in 10 ml. of dry thiophene-free benzene. After standing for 4 hours at 0 C. the reaction mixture was gently heated to 20 C. and kept at this temperature for 12 hours. Samples were taken from the reaction mixture. It appeared by icdometric titration that 1.90 m. at. oxygen per mol compound was consumed.

From the remaining quantity of reaction mixture the precipitated phthalic acid was filtered off and the filtrate obtained was washed successively with a 10% solution of sodium bicarbonate and water, dried on Na SO and after filtering evaporated to dryness 0.88 g. of a substantially colorless resin of 17(20)-epoxy-20-formoxy-retropregn-4-en-3-one was thus obtained, which could not be caused to crystallize.

The hydrolysis of the latter compound was carried out by preparing a solution of the substance in 150 ml. of ethanol (95%) at 30 C. with 35 ml. of aqueous 2.0 N sodium hydroxide solution at room temperature, the reaction mixture assuming a clear yellow color. After standing two hours, without cooling or heating, at room temperature, neutralisation of this reaction mixture with 6 ml. of acetic acid was carried out. The light-yellow solution thus obtained was concentrated at the lowest possible temperature in a water-jet pump vacuum, to about 60 ml. after which 100 ml. of water was added. The oil which separated out was dissolved in two extractions in ether and the ether solution, after having been washed with a diluted bicarbonate solution and water and dried on Na sO was filtered. By evaporating the filtrate to dryuess 580 mgs. of crystalline residue was obtained,

E1 3 max. 242.5 m =504 After three recrystallizations from ethanol at C. 118 mg. of hard crystals of 17u-hydroxy-retro-progesterone were obtained with a melting point of 222-225 C. and the following additional analytical values:

E1 r max. 242 m :500, 242 m .=16,-EO0

Calculated for C l-1 0 (330.45 )1 C, 76.32%; H, 9.15%. Found: C, 76.07%, 75.84%; H, 9.14%, 9.10%.

The infrared spectrum exhibited bands inter alia at 3369 cm? (strong, hydroxyl band), 1697 cmf (strong, unconjugated keto group), 1643 cm.- (strong, conjugated keto-group), 1610 cm. (fairly strong, double bond), 1354 cm. 1232 cmr 928 cm. and 858 cmr (b) A solution of 2.77 g. of bromine in 34 ml. of methylene chloride was added dropwise to a well stirred solution of 6.5 g. of 22-(N-piperidyl)-retro-bisnorchola-4,6, 20(22)-trien-3-one in 320 ml. of methylene chloride at 55 C. The temperature was then raised to about 0 C. and 40 ml. of water was added. This reaction mixture was stirred intensively at 20 C. for two hours. Subsequently the methylene chloride solution was separated off and washed with two 110 ml. portions of water. After drying, 13.5 ml. of dry pyridine were added to this solution and the methylene chloride was distilled off in vacuo. The residue was heated-after the addition of 33.5 ml.

of pyridine-at 70 C. for one hour and then at C. for half an hour. Pyridine was distilled off in vacuo and the residue dissolved in methylene chloride. After washing with 2 N hydrochloric acid solution, water, a solution of sodium carbonate and with water the solution was dried and the solvent evaporated. The residue, 4.86 g., was crystallized from acetone to give 2.41 g. of a sufficiently pure retro-bisnorchola-4,6,17(20)-trien-3-one-22- al. Repeated recrystallization from acetone furnished an analytically pure sample, having the following analytical values:

Melting point 2l72l9 C. A max. =281 mu, e=30,000. Calculated for 0 11 0 (324.56): C, 81.44%; H, 8.69%. Found: C, 81.6%, 81.5%; H, 8.5%, 8.6%.

The infrared absorption spectrum showed bands inter alia at 1655, 1616 and 1574 cm.-

(c) A solution of 15.0 g. of retro-bisnorchola-4,6,17- (20)-trien-3-on-22-al in 150 ml. of ethyl acetate and 150 ml. of benzene was mixed with a solution of 20.2 g. of mono-perphthalic acid in 450 ml. of ethyl acetate. The resultant solution was stored at room temperature for several hours together with a similar solution containing no aldehyde. The reaction progress was followed by an iodometrical estimation of the active oxygen in both solutions. After 16 hours about 1.7 atoms of oxygen per mol of aldehyde had been taken up. The reaction mixture was then filtered and washed with a solution of sodium bicarbonate and with water. After drying the solvents were evaporated and 16.4 g. of a resin were obtained (17(20)- epoxy-20-formoxy-retro-pregna-4,6-dieu-3-one) This resin was dissolved in three litres of ethanol and 700 ml. of a 2 N sodium hydroxide solution were added. This mixture was kept at 30 C. for 1% hours and then neutralised by the addition of ml. of acetic acid. The solution was concentrated in vacuo to a volume of about 700 ml. and, after addition of 1.4 l. of water, extracted with methylene chloride. The extract was washed with sodium bicarbonate solution, with water and dried. After removal of the solvent in vacuo 11.8 g. of a resinous residue were obtained. Crystallization from ethanol furnished 5.69 g. of 6-dehydro-17a-hydroxy-retro-progesterone. After two recrystallizations this substance was obtained in a pure state. (x max.=286 mu, e=25,100).

According to the method described in the Examples 5(a) and 5 (c) the following compounds are prepared:

Z-methyl-17a-hydroxy-retro-progesterone from 2methylretro bisnorchola-4, 1-7 (20 -dien-3 -on-22-a1; 1-dehydro-17a-hydroxy-retro-progesterone from retrobisnorchola- 1,4, 17 20) -trien-3-on-22-al; 6-fluoro-17m-hydroxy-retro-progesterone from 6-fluororetro-bisnorchola-4, 17 (20) -dien-3 -on-22-al; 4-chloro-17a-hydroxy-retro-progesterone from 4-chlororetro-bisnorchola-4, 17 (20) -dien-3-on-22-al; 6-methyl-17a-hydroxy-retro-progesterone from 6-methylretro-bisnorchola-4,17(20)-dien-3-on-22-al; 6,17wdihydroxy-retro-progesterone from 6-hydroxyretro-bisnorchola-4,17(20)-dien-3-on-22-al; 6-methyl-9-fluoro-1 1, 17a-dihydroxy-retro-progesterone from 6-methyl-9-fluoro-11-hydroxy-retrobisnorchola- 4,17(20)-dien-3-on-22-al; 17u-hydroxy-retro-pregnane-3,20-dione from retrobisnorchol- 1 7 20) -3n-3 -on-22-al; 1-dehydro-16-methyl-17a-hydroxy-retro-progesterone from 16-methyl-retro-bisnorchola-1,4, 17 (20) -trien- 3-on-22-al; 17ahydroxy-retro-pregn-l-ene-3,20-dione from 3-ketoretro bisnorchola-L 17 (20) -dien-3 -on-22-al; 3,17tx-dihydroxy-retro-pregnan-20-one from 3-hydroxyretro-bisnorchol-17 (20) -en-22-al.

(d) A mixture of 3.70 g. of retro bisnorchola-4,6,17-

(20)-trien-3-one-22-al, 5.9 g. of sodium cyanide and 37 mls. of dry methanol was treated at -20 C., while stirring with a mixture of 5.3 ml. of acetic acid and 37 ml. of

.at 80 C. with 1.3 mols of ozone/mol of aldehyde.

At 80 C. there were added to the stirred ozonisation mixture 12 g. of trioxymethylene and then the temperature was raised to room temperature. After filtration from trioxymethylene the next day, the solution was washed with dilute sodium hydroxide solution, dilute hydrochloric acid solution and water. After drying, the solvent was evaporated and 2.93 g. of a crystalline residue was obtained. Recrystallization from acetone gave 1.20 g. of retro-androsta-4,6-diene-3,17-dione. By recrystallization from acetone an analytically pure sample was obtained. The analytical values of this material were:

Melting point 189190 C. A max.=285 ma, e=25,400. Calculated for C1gH24O2 (284.40): C, 80.24%; H, 8.51%. Found: C. 80.2%, 80.4%; H, 8.4%, 8.7%.

In the infrared absorption spectrum strong bands are found at 1735, 1652 and 1623 cmf According to this process there are prepared 6-methyl-retro-androsta-4,6-diene-3,17-di0ne from 6-methyl-retro-bisnorchola-4,6, 17 (20 -trien-3-on-22-al,

2-fiuoro-retro-androsta-4,6-diene-3,17-dione from 2-fluororetro-bisnorchola-4,6, 1 7 (20 -trien-3-on-22-al,

2-fluoro-retro-androsta-1,4,6-triene-e,17-dione from 2-fiuoro-retro-bisnorchola-l ,4,6, 17 20 -tetraen-3 -on-22-al, and

16-methyl-retro-androsta-4,6-diene-3,17-dione from 16- methyl-retro-bisnorchola-4,6, 17 (20) -trien-3-on-22-al.

Example 6 2 g. of palladium on calcium carbonate (produced according to Vogel, page 891) was shaken with 40 ml. of pyridine dried on potassium-hydroxide and subsequently distilled in a hydrogen atmosphere until the gas absorption ceased. To the catalyst suspension thus produced a solution of 1.88 g. of 17a-ethinylretro-testosterone in 50 ml. of pyridine was then added, further 10 ml. of solvent being subsequently used for rinsing. Hydrogen was passed into the solution while under a small excess pressure and with shaking. Within about 10 minutes 110% of the theoretical quantity of hydrogen was absorbed and the hydrogenation was stopped.

The catalyst was filtered off and the filter was washed with methylene chloride. After dilution with petroleum ether, the pyridine was washed away with 2 N sulphuric acid, the organic layer becoming colorless. Subsequently the solution was thoroughly washed with water to a neutral reaction, dried on sodium sulphate, filtered and the solvent was evaporated. The residue (1.82 g.) was crystallized from a mixture of acetone and hexane at room temperature. The crystallizate had a melting point of 141- 142144.5 C. Recrystallization from the same mixture yielded finally 1.17 g. of 17a-vinyl-retro-testosterone with a melting point of 142.5-144145.5 C.

A small quantity of this compound was recrystallized to obtain a constant melting point and the following analytical 'values:

Melting point: 143.5144.5-146 C.

The infrared absorption spectrum, measured in KBr, exhibits maxima, inter alia, at 1658, 1620, 1413, 1068, 923 and 876 cm.- Since no band for an OH group was found at 3300 to 3400 cm. the spectrum was also determined in CS (compensated). The following bands were found: 3570 (weak), 1676 (strong), 1617, 1008, 993, 920 and 863 CHIS-1.

EYE (A maximurn=242 m i) 555 and 557 (methanol),

e (212 m =17,50O

40 Found: c, 79.59. 79.99, 80.07, 80.14; H, 9.79, 9.58, 9.78, 9.74. Calculated for 0 ,191, 0 314.47 0, 80.21; H, 9.62.

By this process the following compounds, listed with their starting materials are prepared: l7a-allyl-retro testosterone from 17m-propinyl-retro-testosterone, 6-fluoro-l7a-vinylretro-testosterone from 6-fluoro-17u-ethinylretro testosterone; 2 fluoro-17a-vinyl-retro-testosterone from 2 fiuoro 17rz-ethinyl-retro-testosterone; 6-methyl- 17cc allyl-retro-testosterone from 6-methy1-17a-propinylretro testosterone and 3-desoxy-17a-allyl-retro-testosterone from 3-desoxy-17a-propinyl-retro-testosterone.

Example 7 To a solution of g. of lurnista-4,6,22-trien-3-one and 55 ml. of freshly distilled ethyl formate in 1200 ml. of benzene were then added 16.5 g. of sodium hydride. The mixture was then kept at room temperature in a nitrogen atmosphere for three days. After two hours a greenish jelly was formed, which gradually became paste-like.

After the three days, the resultant sodium salt of 2- hydroxymethylene-lumista-4,6,22-triene-3-one was filtered off and the solid substance was dried in vacuo.

After the free hydroxymethylene compound was obtained from the sodium salt, crystallization from methanol was carried out and the yield of Z-hydroxymethylenelumista-4,6,22-trien-3-one was -70%. The substance thus obtained was found to be a hydrated form of the expected substance, since by drying in vacuo at 60 C. the substance assumed a dehydrated form.

The hydrate had the following analytical values:

Melting point (60 to )119-122 C. (vacuo). During melting the substance gives oif water.

Found: C, 79.11, 79.24; H, 10.10, 10.21. Calculated for C29H4202'H20: C, H,

The infrared spectrum shows, inter alia, bands at 3360,

1674, 1625, 1594, 1225, 1200, 1107, 984, 967 and 882' cmr Weak acid: 296 m 454, 322 m 354.

Weak alkaline: 255 III/.L, 308, 290 m 422, 263 m 310, 390 m 224.

The anhydrous substance had the following analytical values:

Melting point 121-122123.5 C. (vacuo). Found: C, 82.29, 82.26; H, 10.02, 10.12; 0, 7.08, 7.71. Calc. for C H O C, 82.41; H, 10.02; 0, 7.57.

The infrared spectrum shows inter alia bands at 1641, 1621, 1560, 1196, 986 and 874 cmr- X ll...

Weak acid: 296 m 463, 323 m 362. Weak alkaline: 255 m 319, 263 m 320, 290 my, 428,

In the same manner as described above the 1umista-4, 22-diene-3-one is converted into the 2-hydroxymethylene compound. This 2-hydroxymethylene-lumista-4,22-diene- 3-one had the following analytical values:

7 Melting point 131(s)134135 C. Found: C, 81.72, 81.60; H, 10.42, 10.46; 0, 7.94, 7.93. Calc. for C H O C, 82.02; H, 10.44; 0, 7.54.

The infrared spectrum shows inter alia bands at 1641,

1566, 1199, 974 and 883 CIIITI.

Weak acid: 256 m 296, 300 m 202. Weak alkaline: 243 m 373, 358 my, 258.

(b) 108 g. of the sodium salt of Z-hydroxymethylenelumista-4,6,22-trien-3-one was dissolved, while heating, in heated 3.2 l. of anhydrous ethanol. The mixture was then cooled and dry nitrogen was slowly introduced. When the temperature of 10 C. was reached, perchlory1 

1. A 10A-METHYL, 9B, 8B, 13B, 14A HORMONAL STEROID OF THE ANDROSTANE SERIES WHEREIN THE SUBSTITUENTS AT THE 17B AND 17A POSITIONS ARE SELECTED FROM ONE OF THE FOLLOWING COMBINATIONS: (A) THE SUBSTITUENT AT 17B IS OR'' WHEREIN R'' IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL AND ACYL AND THE SUBSTITUENT AT 17A IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF ALKYL OF 2-6 CARBON ATOMS, ALKYNYL OF 2-6 CARBON ATOMS AND ALKENYL OF 2-6 CARBON ATOMS, (B) THE SUBSTITUENT AT THE 17B POSITION AND THE SUBSTITUENT AT THE 17A POSITION ARE EACH SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HYDROXY AND --O-ACYL WITH THE PROVISO THAT THE SUBSTITUENT AT THE 17B POSITION IS HYDROGEN ONLY WHEN THE SUBSTITUENT AT 17A POSITION IS OTHER THAN HYDROGEN AND THE SUBSTITUENT AT THE 17B POSITION IS OTHER THAN HYDROGEN WHEN THE SUBSTITUENT AT THE 17A POSITION IS HYDROGEN AND (C) THE SUBSTITUENT AT THE 17A POSITION TOGETHER WITH THE SUBSTITUENT AT THE 17B POSITION FORMING THE OXO GROUP.
 4. A HORMONAL STEROID OF CLAIM 1 CORRESPONDING TO THE FORMULA: 